DESCRIPTION STRESS EDITING OF CAMKIIδ PRIORITY CLAIM This application claims benefit of priority to U.S. Provisional Application Serial No. 63/352,804, filed June 16, 2022, the entire contents of which are hereby incorporated by reference. REFERENCE TO A SEQUENCE LISTING This application contains a Sequence Listing XML, which has been submitted electronically and is hereby incorporated by reference in its entirety. Said XML Sequence Listing, created on June 14, 2023, is named UTFD.P4100WO.xml and is ~109 kilobytes in size. BACKGROUND 1. Field [0001] The present invention relates generally to the fields of molecular biology, medicine, and genetics. More particularly, it concerns compositions and uses thereof for genome editing to eliminate stress responses by CaMKIIδ in cells such as cardiomyocytes. 2. Description of Related Art [0002] CRISPR-Cas9 gene editing is being developed as a therapeutic approach to correct monogenic mutations causing hereditary diseases (Liu & Olson, 2022; Chemello et al., 2021; Richter et al., 2020; Amoasii et al., 2018; Amoasii et al., 2019; Koblan et al., 2021). However, most CRISPR-Cas9 editing strategies are focused on correction of specific genetic mutations that occur in a small subset of patients, limiting broader applications of the approach, whereas targeting a broader range of adult patients with cardiovascular disease, the leading cause of worldwide morbidity and mortality, would be much more useful (Virani et al., 2021). [0003] Ca ²⁺ /calmodulin-dependent protein kinase IIδ (CaMKIIδ) is a central regulator of cardiac signaling and function (Beckendorf et al., 2018). However, chronic overactivation of CaMKIIδ causes several cardiac diseases in humans and mice, including ischemia/reperfusion (IR) injury, heart failure, hypertrophy, and arrhythmias (Neef et al., 2010; Backs et al., 2009; Lebek et al., 2020; Zhang & Brown, 2004; Ling et al., 2013; Luo et al., 2013; Nassal et al., 2020; Pellicena & Schulman, 2014). Mechanistically, CaMKIIδ overactivation in the heart has been linked to disturbances in Ca ²⁺ homeostasis, inflammation, apoptosis, and fibrosis, leading to cardiac dysfunction (Neef et al., 2010; Backs et al., 2009; Lebek et al., 2020; Zhang & Brown, 2004; Ling et al., 2013; Lebek et al., 2018). Oxidation of two methionine residues, Met281 and Met282, located in the regulatory domain of CaMKIIδ, promotes hyperactivation of the kinase by preventing association of the catalytic domain with the autoinhibitory region (Erickson et al., 2008). Modification of these methionine residues to other amino acids prevents oxidation and overactivation of CaMKIIδ, thereby conferring cardioprotection as shown in MMVV knock-in mice, where both methionine residues were replaced with valines in the germline (Luo et al., 2013; Erickson et al., 2008; Purohit et al., 2013). This genetic modification did not cause adverse effects. Both methionines are encoded by exon 11, which is not subject to alternative splicing, so targeting the oxidative activation sites would affect all CaMKIIδ splicing variants (for example CaMKIIδB, δC, and δ9 as the major cardiac variants) (Zhang et al., 2019). SUMMARY [0004] In accordance with the present disclosure, there is provided a single guide RNA (sgRNA) comprising a targeting nucleic acid sequence that targets a CaMKIIδ regulatory domain. The sgRNA may target Met281 and/or Met282 and/or His283 of CaMKIIδ. The sgRNA may comprise the sequence: [0005] Also provided is a composition comprising a sgRNA that targets a CaMKIIδ regulatory domain and a base editor. The base editor may be an adenine base editor (ABE). The sgRNA may be sgRNA as set forth in the preceding table or defined in paragraph [0003]. The base editor may comprise a CRISPR/Cas nuclease linked to an adenosine deaminase, such as wherein the CRISPR/Cas nuclease is catalytically impaired and/or wherein the CRISPR/Cas nuclease is a Cas9 nuclease, such as wherein the Cas9 nuclease is isolated or derived from Streptococcus pyogenes (spCas9), Streptococcus pyogenes (spRY), Staphylococcus aureus (SaCas9), Staphylococcus auricularis (SauCas9), Streptococcus pyogenes (spRY) or Staphylococcus lugdunensis (SlugCas9). [0006] Also provided is a nucleic acid comprising a sequence encoding a first sgRNA of as set out in the table above, a sequence encoding a base editor, a sequence encoding a first promoter, wherein the first promoter drives expression of the sequence encoding the base editor, and a sequence encoding a second promoter, wherein the second promoter drives expression of the sequence encoding the first sgRNA. The base editor may be an adenine base editor (ABE). The base editor may comprise a CRISPR/Cas nuclease linked to an adenosine deaminase, such as wherein the CRISPR/Cas nuclease is catalytically impaired. The CRISPR/Cas nuclease may be a Cas9 nuclease, such as wherein the Cas9 nuclease is isolated or derived from Streptococcus pyogenes (spCas9), Streptococcus pyogenes (spRY), Staphylococcus aureus (SaCas9), Staphylococcus auricularis (SauCas9), Streptococcus pyogenes (spRY) or Staphylococcus lugdunensis (SlugCas9). [0007] The at least one of the sequences encoding the first promoter and the sequence encoding the second promoter may comprise a cell-type specific promoter, such as a cardiomyocyte-specific promoter, in particular a cardiac troponin T (cTnT) promoter. The sequence encoding the second promoter may comprise a sequence encoding a U6 promoter, an H1 promoter, or a 7SK promoter. [0008] The nucleic acid may comprise a DNA sequence, or an RNA sequence, and/or may further comprise a polyadenosine (polyA) sequence, such as a mini polyA sequence. [0009] In other embodiments, there are provided: a cell comprising the nucleic acids as defined herein, a composition comprising the nucleic acids as defined herein, a cell comprising such a composition, a composition comprising such a cell. [0010] In yet another embodiment, there is provided a vector comprising the nucleic acids as described herein. The vector may further comprise a sequence encoding an inverted terminal repeat (ITR) of a transposable element, such as a transposon (e.g., a Tn7 transposon). The vector may further comprise a sequence encoding a 5’ ITR of a T7 transposon and a sequence encoding a 3’ ITR of a T7 transposon. The vector may be a non-viral vector, such as a plasmid, or a viral vector, such as an adeno-associated viral (AAV) vector or an adenoviral vector. The AAV vector may be replication-defective or conditionally replication defective and/or may be a recombinant AAV vector. The AAV vector may comprise a sequence isolated or derived from an AAV vector of serotype 1 (AAV1), 2 (AAV2), 3 (AAV3), 4 (AAV4), 5 (AAV5), 6 (AAV6),7 (AAV7), 8 (AAV8), 9 (AAV9), 10 (AAV10), 11 (AAV11) or any combination thereof, such as wherein the AAV vector comprises a sequence isolated or derived from an AAV2 and a sequence isolated or derived from an AAV9. The vector may be optimized for expression in mammalian cells, such as optimized for expression in human cells. [0011] In a further embodiment, there is provided a composition comprising the vector as defined herein, optionally further comprising a pharmaceutically acceptable carrier. The vectors of the present disclosure, or the compositions comprising such vectors may comprise a trans-splicing intein system. Also provided are cells comprising the vectors as described herein or the compositions comprising the vectors. The cells may be human cells, such as where the cells are cardiomyocytes or human cardiomyocytes, or the cells or human cells may be induced pluripotent stem (iPS) cells. A composition comprising such cells is also provided. [0012] In yet a further embodiment, there is provided a method for editing a sequence in the regulatory domain of CaMKIIδ, the method comprising contacting a cell with a vector/composition as described here under conditions suitable for expression of the first sgRNA and the adenine base editor, wherein the first sgRNA forms a complex with the adenine base editor, wherein the complex modifies edits a sequence in the regulatory domain of CaMKIIδ thereby blocking the oxidative stress response of CaMKIIδ. Also provided is a cell produced by this method, such as a cardiomyocyte, e.g., a stem-cell derived cardiomyocyte. [0013] A still further embodiment comprises a method of treating or preventing cardiac injury, such as ischemia/reperfusion injury, in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition as described herein. The composition may be administered locally, such as directly to cardiac tissue (e.g., by an infusion or injection), or administered systemically (e.g., by an intravenous infusion or injection). [0014] Following administration of the composition, the subject may exhibit improved Ca ²⁺ transient amplitude, decreased arrhythmia, decreased ventricular dilation, improved cardiac function (improved ejection fraction, fractional shortening), or a combination thereof. Also, following administration of the composition, the subject may not exhibit cellular Ca ²⁺ dysregulation. The subject may be a neonate, an infant, a child, a young adult, or an adult, a male, or a female. [0015] Use of a therapeutically effective amount of a composition as described herein for treating or preventing cardiac injury, such as ischemia/reperfusion injury, in a subject in need thereof, is provided. [0016] In an additional embodiment, there is provided an induced pluripotent stem cell comprising an edited CaMKIIδ gene encoding Valine 281, optionally comprising an edited CaMKIIδ gene encoding Valine 281, Valine 282 and Arginine 283. [0017] In one embodiment, provided herein are methods for screening at least one candidate agent in a mouse according to any one of the present embodiments, comprising administering one or more candidate agent to the mouse. The at least one candidate agent may be screened for its ability to improve left ventricular function. The at least one candidate agent may be screened for its ability to rescue cardiac chamber size. The at least one candidate agent may be screened for its ability to increase life span. The candidate agent may comprise a sgRNA of any one of the present embodiments. [0018] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS [0019] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. [0020] Figs.1A-L. Genomic editing of CaMKIIδ in human iPSC-cardiomyocytes. (Fig.1A) Schematic of CaMKIIδ and its three domains. Both critical methionines (Met281 and Met282) are located in the regulatory domain. Upon oxidative stress, these methionines are oxidized, resulting in increased CaMKII activity and cardiac disease. Using CRISPR-Cas9 adenine base editing, the inventors identified sgRNA1, which edited only c.A841G (p.M281V; sgRNA1), and sgRNA6, which edited c.A841G (p.M281V), c.A844G (p.M282V), and c.A848G (p.H283R; sgRNA6), thereby preventing CaMKII activation upon oxidative stress. (Fig.1B) Sequence of a segment of exon 11 of CaMKIIδ genomic DNA encoding part of the regulatory domain of CaMKIIδ (SEQ ID NO: 84). Alignment of sgRNA1 and sgRNA6 with CaMKIIδ. PAM sequences for sgRNA1 and sgRNA6 are in blue and green, respectively. Both ATGs encoding methionines are highlighted in yellow. Adenines within the sequences of sgRNA1 (blue) and sgRNA6 (green) are numbered (starting from the PAM). (Fig. 1C) Percentage of adenine (A) to guanine (G) editing in human iPSCs for each adenine in sgRNA1 after base editing with ABE8e and sgRNA1, as determined by Sanger sequencing. (Fig. 1D) Percentage of adenine (A) to guanine (G) editing in human iPSCs for each adenine in sgRNA6 after base editing with ABE8e and sgRNA6, as determined by deep amplicon sequencing. (Fig. 1E) Western blot analysis of oxidized CaMKII (specific antibody), autophosphorylated CaMKII (specific antibody), total CaMKII, and GAPDH in human wildtype (WT), sgRNA1, and sgRNA6 iPSC-CMs for control group and after simulated ischemia/reperfusion (IR). (Fig. 1F) Mean densitometric analysis for oxidized CaMKII normalized to total CaMKII in control and post-IR iPSC-CMs (n=5 independent iPSC-CM differentiations). (Fig. 1G) Mean densitometric analysis for autophosphorylated CaMKII normalized to total CaMKII in control and post-IR iPSC-CMs (n=5 independent iPSC-CM differentiations). (Fig.1H) Scatter bar plot showing mean CaMKII activity in control and post-IR iPSC-CMs and in lysates of WT post- IR iPSC-CMs in presence of the CaMKII inhibitor AIP (n=5 independent iPSC-CM differentiations). (Fig. 1I) Western blot analysis of ryanodine receptor type 2 (RyR2) phosphorylation at the CaMKII site (serine 2814), total RyR2, and GAPDH in control and post- IR iPSC-CMs (n=5 independent iPSC-CM differentiations). (Fig. 1J) Mean densitometric analysis for phosphorylated RyR2 normalized to total RyR2 in control and post-IR iPSC-CMs (n=5 independent iPSC-CM differentiations). (Fig.1K) Mean Ca ²⁺ transient amplitude for each group (based on the number of cardiomyocytes). (Fig.1L) Percentage of iPSC-CMs showing arrhythmias, as measured by epifluorescence microscopy. Statistical comparisons are based on one-way ANOVA post-hoc corrected by Holm-Sidak (Figs. 1F-H and Figs. 1J-K) and on Fisher’s exact test (Fig. 1L). Data are presented either as individual data points with means ± SEM or as percent of cells (Fig.1L). [0021] Figs. 2A-E. CaMKIIδ base editing improves cardiac function in vivo post- IR. (Fig. 2A) Experimental design for subjecting mice to IR, injecting AAV-ABE-sgRNA6 for CaMKIIδ editing in vivo and monitoring heart function by echocardiography and cardiac magnetic resonance imaging (MRI). The AAV9 delivery system carrying the CRISPR-Cas9 base editing components with a split-intein trans-splicing system is shown. (Fig. 2B) Time course of fractional shortening for each group before IR as well as 24 hours, 1 week, 2 weeks, and 3 weeks post-IR (n=8 mice for each group; x-axis not shown to scale). (Fig. 2C) Representative M-mode recordings of hearts of a sham-treated mouse, a mouse subjected to IR, a mouse subjected to IR with intracardiac injection of a control virus, and a mouse subjected to IR with intracardiac injection of AAV-ABE-sgRNA6 (IR+Edit) at three weeks post-IR. (Fig. 2D) Mean left ventricular end-diastolic diameter 3 weeks after IR (n=8 mice for each group). (Fig.2E) Mean left ventricular ejection fraction determined by cardiac MRI 4 weeks post-IR (n=5 mice for each group). All replicates are individual mice. Statistical comparisons are based on two-way (Fig.2B) and one-way (Figs.2D-E) ANOVA post-hoc corrected by Holm-Sidak. Data are presented as means ± SEM. [0022] Figs. 3A-M. Analysis of mouse hearts after CaMKIIδ in vivo genomic editing by administration of AAV-ABE-sgRNA6. (Fig. 3A) Percentage of adenine (A) to guanine (G) editing of DNA and cDNA for each adenine along sgRNA6 in the myocardium of mice treated with AAV-ABE-sgRNA6, as determined by deep amplicon sequencing. (Fig.3B) Spatial analysis of adenine (A) to guanine (G) editing efficiency at cDNA level for each adenine along sgRNA6 in the anterior and the inferior cardiac wall of mice injected with AAV- ABE-sgRNA6 in the anterior cardiac wall, as determined by Sanger sequencing. (Fig. 3C) Sequencing of a TOPO-TA clone shows in vivo editing (SEQ ID NO: 85) of CaMKIIδ gene (SEQ ID NO: 86) at the cDNA level. (Fig.3D) Percentage of transcriptome-wide adenine (A) to inosine (I) editing in the myocardium of sham-treated, IR, IR treated with a control virus, and IR edited mice. (Fig.3E) Western blot analysis of oxidized CaMKII, autophosphorylated CaMKII, total CaMKII, and GAPDH for all groups. (Fig.3F) Mean densitometric analyses for oxidized CaMKII normalized to total CaMKII for sham-treated, IR, IR treated with a control virus, and IR edited mice. (Fig. 3G) Mean densitometric analyses for autophosphorylated CaMKII normalized to total CaMKII for all groups. (Fig. 3H) Mean CaMKII activity for all groups; and for lysates of IR and IR+Control Virus mice both in presence of the CaMKII inhibitor AIP. (Fig. 3I) Western blot analysis of ryanodine receptor type 2 (RyR2) phosphorylation at the CaMKII site (serine 2814), total RyR2, and GAPDH for all groups. (Fig. 3J) Mean densitometric analysis for phosphorylated RyR2 normalized to total RyR2 for all groups. (Fig. 3K) Heat map of 209 differentially expressed genes between mice subjected to IR and either injected with a control AAV9 (n=3) or AAV-ABE-sgRNA6 for editing of the CaMKIIδ gene (n=4). (Fig.3L) Gene ontology terms associated with the 101 genes upregulated in mouse hearts injected with AAV-ABE-sgRNA6 compared to mice receiving control AAV9. (Fig.3M) Gene ontology terms associated with the 108 genes downregulated in mouse hearts injected with AAV-ABE-sgRNA6 compared to mice injected with control AAV9. All replicates are individual mice. Statistical comparisons are based on one-way ANOVA post-hoc corrected by Holm-Sidak. Data are presented as individual data points with means ± SEM. [0023] Figs. 4A-D. Genomic editing of CaMKIIδ prevents cardiac cell death and fibrosis after IR. (Fig.4A) Immunohistochemistry of TUNEL (green, arrows), Hoechst 33342 (blue, for all nuclei), and cardiac troponin (red) in representative heart sections of mice subjected to sham-treatment, IR, IR treated with a control AAV9, and IR treated with AAV- ABE-sgRNA6 (IR+Edit; scale bar 20 μm). (Fig.4B) Mean percentage of TUNEL positive cells in each group. (Fig.4C) Whole transverse cross-sections of trichrome stained hearts for each group (scale bar 500 μm). (Fig. 4D) Mean percentage of fibrotic cardiac tissue in each group. Replicates are individual mice. Statistical comparisons are based on one-way ANOVA post- hoc corrected by Holm-Sidak. Data are presented as individual data points with means ± SEM. [0024] Figs.5A-D. Screening of various genomic editing strategies of CaMKIIδ in HEK293 cells using transfection. (Fig.5A) Percentage of adenine (A) to guanine (G) editing in human HEK293 cells at c.A841 (p.M281) for sgRNAs 1 to 6 combined with either ABEmax or ABE8e that were fused to either SpCas9 or SpRY. (Fig.5B) Percentage of A to G editing in human HEK293 cells at c.A844 (p.M282) for all tested editing strategies. (Fig.5C) Percentage of A to G editing in HEK293 cells for each adenine in sgRNA1 following base editing with ABE8e fused to SpCas9. (Fig. 5D) Percentage of A to G editing in HEK293 cells for each adenine in sgRNA6 following base editing with ABE8e fused to SpRY. Percentage of editing is based on Sanger sequencing. Adenines along the sequence of either sgRNA1 (Fig. 5C) or sgRNA6 (Fig.5D) are numbered starting from the PAM. Data are presented as individual data points with means ± SEM. [0025] Figs.6A-G. Analysis of potential genomic off-target editing in human iPSC using deep amplicon sequencing. (Fig.6A) Percentage of iPSC clones (n=12) that are either wildtype, heterozygous or homozygous for c.A841G (p.M281V), c.A844G (p.M282V), and c.A848G (p.H283R), as determined by Sanger sequencing. (Fig. 6B) Sequence of sgRNA6 (SEQ ID NO: 31) and the corresponding DNA sequences and PAMs of other CaMKII isoforms (α, β, and γ) (SEQ ID NOs: 87-89) and of the top eight potential off-target sites predicted by CRISPOR (SEQ ID NOs: 60-67). Bases that are different from sgRNA6 are highlighted in yellow. Adenines along the sequence are numbered starting from the PAM. (Fig. 6C) Percentage of adenine (A) to guanine (G) editing for each adenine in the CaMKIIα DNA sequence corresponding to sgRNA6. (Fig.6D) Percentage of A to G editing for each adenine in the CaMKIIγ DNA sequence corresponding to sgRNA6. (Fig. 6E) Percentage of A to G editing for each adenine in the CaMKIIβ DNA sequence corresponding to sgRNA6. (Fig.6F) Quantification of CaMKIIβ and CaMKIIδ mRNA expression in human iPSC-CMs. (Fig. 6G) Percentage of A to G editing for each adenine (ordered from 5’ to 3’) in the DNA sequences of the top eight potential off-target sites, starting with #1. Replicates are either human iPSCs (Fig.6C, Fig.6D, Fig.6E, Fig.6G) from three independent nucleofections with sgRNA6 and ABE8e fused to SpRY, or human cardiomyocytes from three independent differentiations (Fig. 6F). One wildtype iPSC sample was included as a negative control. The red line at 0.2% represents the threshold that has previously been used to distinguish from unspecific background guanine signal (Clement et al., 2019). Statistical comparison is based on an unpaired Student’s t test (Fig.6F). Data are presented as individual data points with means ± SEM or as individual data points with means, as appropriate. [0026] Figs.7A-E. Western blot analyses of human iPSC-cardiomyocytes post-IR. (Fig.7A) Mean densitometric analysis of oxidized CaMKII normalized to GAPDH in human wildtype (WT), sgRNA1, and sgRNA6 iPSC-CMs for control group and following simulated ischemia/reperfusion (IR). (Fig. 7B) Mean densitometric analysis for autophosphorylated CaMKII normalized to GAPDH. (Fig. 7C) Mean densitometric analysis for total CaMKII normalized to GAPDH. (Fig. 7D) Mean densitometric analysis for ryanodine receptor type 2 (RyR2) phosphorylation at the CaMKII site (serine 2814) normalized to GAPDH. (Fig. 7E) Mean densitometric analysis for total RyR2 normalized to GAPDH. These data represent further densitometric analyses related to the Western blots presented in the main manuscript. Representative Western blots can be found in Fig.1E (for Fig.7A, Fig. 7B, and Fig.7C) and Fig.1I (for Fig.7D and Fig.7E). Statistical comparisons are based on five independent iPSC- CM differentiations per group and were performed with one-way ANOVA post-hoc corrected by Holm-Sidak. Data are presented as individual data points with means ± SEM. [0027] Figs.8A-D. CaMKIIδ editing preserves cellular Ca ²⁺ homeostasis in human iPSC-cardiomyocytes post-IR. (Fig.8A) Representative Ca ²⁺ transients for human wildtype (WT), sgRNA1, and sgRNA6 iPSC-CMs for control group and following simulated ischemia/reperfusion (IR), as measured by epifluorescence microscopy. (Fig. 8B) Mean diastolic Ca ²⁺ levels. (Fig. 8C) Mean relaxation time to 50% baseline. (Fig. 8D) Mean relaxation time to 80% baseline. Statistical comparisons are based on the number of cardiomyocytes and were performed with one-way ANOVA post-hoc corrected by Holm- Sidak. Data are presented as individual data points with means ± SEM. [0028] Figs. 9A-C. Testing of mouse-sgRNA6 in mouse N2a cells. (Fig. 9A) Sequence of mouse CaMKIIδ gene (SEQ ID NO: 90) encoding part of the regulatory domain and alignment of mouse-sgRNA6 (PAM sequence in green). Both ATGs encoding methionines are highlighted in yellow. Adenines along the sequence of sgRNA6 are numbered (starting from the PAM). Bases that are different from the human sequence are marked with an asterisk. Mouse-sgRNA6 sequence has 95% homology with the human-sgRNA6 sequence. (Fig. 9B) Percentage of adenine (A) to guanine (G) editing in mouse N2a cells for each adenine in sgRNA6 following base editing with ABE8e and mouse-sgRNA6, as determined by Sanger sequencing. (Fig.9C) Representative Sanger sequencing chromatogram for editing the mouse genome with sgRNA6 (SEQ ID NO: 91). Data are presented as individual data points with means. [0029] Figs. 10A-E. Evaluation of cardiac function with echocardiography one week before ischemia/reperfusion injury. (Fig. 10A) Mean fractional shortening for sham- treated mice and mice subjected to ischemia/reperfusion (IR) injury with either no injection, injection of a control virus or intracardiac injection of AAV-ABE-sgRNA6 (IR+Edit). (Fig. 10B) Mean left ventricular end-diastolic posterior wall thickness for all groups. (Fig. 10C) Mean left ventricular end-diastolic diameter for all groups. (Fig. 10D) Mean left ventricular end-diastolic volume for all groups. (Fig. 10E) Mean heart rate for all groups. Statistical comparisons are based on eight mice per group and were performed with one-way ANOVA post-hoc corrected by Holm-Sidak. Data are presented as individual data points with means ± SEM. [0030] Figs. 11A-E. Evaluation of cardiac function with echocardiography 24 hours after ischemia/reperfusion injury. (Fig. 11A) Mean fractional shortening for sham- treated mice and mice subjected to ischemia/reperfusion (IR) injury with either no injection, injection of a control virus or intracardiac injection of AAV-ABE-sgRNA6 (IR+Edit). (Fig. 11B) Mean left ventricular end-diastolic posterior wall thickness for all groups. (Fig. 11C) Mean left ventricular end-diastolic diameter for all groups. (Fig. 11D) Mean left ventricular end-diastolic volume for all groups. (Fig. 11E) Mean heart rate for all groups. Statistical comparisons are based on eight mice per group and were performed with one-way ANOVA post-hoc corrected by Holm-Sidak. Data are presented as individual data points with means ± SEM. [0031] Figs. 12A-E. Evaluation of cardiac function with echocardiography one week after ischemia/reperfusion injury. (Fig. 12A) Mean fractional shortening for sham- treated mice and mice subjected to ischemia/reperfusion (IR) injury with either no injection, injection of a control virus or intracardiac injection of AAV-ABE-sgRNA6 (IR+Edit). (Fig. 12B) Mean left ventricular end-diastolic posterior wall thickness for all groups. (Fig. 12C) Mean left ventricular end-diastolic diameter for all groups. (Fig. 12D) Mean left ventricular end-diastolic volume for all groups. (Fig. 12E) Mean heart rate for all groups. Statistical comparisons are based on eight mice per group and were performed with one-way ANOVA post-hoc corrected by Holm-Sidak. Data are presented as individual data points with means ± SEM. [0032] Figs. 13A-E. Evaluation of cardiac function with echocardiography two weeks after ischemia/reperfusion injury. (Fig. 13A) Mean fractional shortening for sham- treated mice and mice subjected to ischemia/reperfusion (IR) injury with either no injection, injection of a control virus or intracardiac injection of AAV-ABE-sgRNA6 (IR+Edit). (Fig. 13B) Mean left ventricular end-diastolic posterior wall thickness for all groups. (Fig. 13C) Mean left ventricular end-diastolic diameter for all groups. (Fig. 13D) Mean left ventricular end-diastolic volume for all groups. (Fig. 13E) Mean heart rate for all groups. Statistical comparisons are based on eight mice per group and were performed with one-way ANOVA post-hoc corrected by Holm-Sidak (Figs. 13A-C and Fig. 13E) and with Kruskal-Wallis test post-hoc corrected by Dunn (Fig.13D). Data are presented as individual data points with means ± SEM. [0033] Figs. 14A-D. Evaluation of cardiac function with echocardiography three weeks after ischemia/reperfusion injury. (Figs.14A) Mean fractional shortening for sham- treated mice and mice subjected to ischemia/reperfusion (IR) injury with either no injection, injection of a control virus or intracardiac injection of AAV-ABE-sgRNA6 (IR+Edit). (Figs. 14B) Mean left ventricular end-diastolic posterior wall thickness for all groups. (Figs. 14C) Mean left ventricular end-diastolic volume for all groups. (Figs.14D) Mean heart rate for all groups. Statistical comparisons are based on eight mice per group and were performed with one-way ANOVA post-hoc corrected by Holm-Sidak. Data are presented as individual data points with means ± SEM. [0034] Figs. 15A-B. Evaluation of cardiac function with cardiac magnetic resonance imaging four weeks after ischemia/reperfusion injury. (Fig. 15A) Mean left ventricular mass for sham-treated mice and mice subjected to ischemia/reperfusion (IR) injury with either no injection, injection of a control virus or intracardiac injection of AAV-ABE- sgRNA6 (IR+Edit). (Fig. 15B) Mean left ventricular end-diastolic volume for all groups. Statistical comparisons are based on five mice per group and were performed with Kruskal- Wallis test post-hoc corrected by Dunn (Fig. 15A) and one-way ANOVA post-hoc corrected by Holm-Sidak (Fig.15B). Data are presented as individual data points with means ± SEM. [0035] Figs.16A-D. Analysis of potential genomic off-targets in mouse tissue using deep amplicon sequencing. (Fig.16A) Mouse sequence of sgRNA6 (SEQ ID NO: 32) and the corresponding DNA sequences and PAMs of other CaMKII isoforms (α, β, and γ) (SEQ ID NOs: 92-94) in the mouse genome. Bases that are different from sgRNA6 are highlighted in yellow. Adenines along the sequence are numbered starting from the PAM. (Fig. 16B) Percentage of cardiac adenine (A) to guanine (G) editing for each adenine in the DNA sequence corresponding to sgRNA6 in different CaMKII isoforms. Mice were either injected with AAV- ABE-sgRNA6 (IR+Edit; for analyses of CaMKIIα, β, and γ) or with a control virus (for analysis of CaMKIIδ). (Fig.16C) Percentage of A to G editing for each adenine in the DNA sequence corresponding to sgRNA6 in the brain (for all CaMKII isoforms), the tibialis anterior muscle (for CaMKIIδ), and the liver (for CaMKIIδ) of mice injected with AAV-ABE-sgRNA6 (IR+Edit). (Fig. 16D) Percentage of A to G editing for each adenine in the DNA sequence corresponding to sgRNA6 in all CaMKII isoforms, measured in wildtype control mice. The red line at 0.2% represents the threshold that has previously been used to distinguish from unspecific background guanine signal (Clement et al., 2019). Data are presented as individual data points with means ± SEM (Figs. 16B-C) or as individual data points with means (Fig. 16D). [0036] Figs. 17A-E. Western blot analyses in mouse myocardium post-IR. (Fig. 17A) Mean densitometric analysis for oxidized CaMKII normalized to GAPDH for sham- treated mice and mice subjected to ischemia/reperfusion (IR) injury with either no injection, injection of a control virus or intracardiac injection of AAV-ABE-sgRNA6 (IR+Edit). (Fig. 17B) Mean densitometric analysis for autophosphorylated CaMKII normalized to GAPDH. (Fig.17C) Mean densitometric analysis for total CaMKII normalized to GAPDH. (Fig.17D) Mean densitometric analysis for ryanodine receptor type 2 (RyR2) phosphorylation at the CaMKII site (serine 2814) normalized to GAPDH. (Fig.17E) Mean densitometric analysis for total RyR2 normalized to GAPDH. These data represent further densitometric analyses related to the Western blots presented in the main manuscript. Representative Western blots can be found in Fig.3E (for Fig.17A, Fig.17B, and Fig.17C) and Fig.3I (for Fig.17D and Fig.17E). Statistical comparisons are based on five mice per group and were performed with one-way ANOVA post-hoc corrected by Holm-Sidak. Data are presented as individual data points with means ± SEM. [0037] Figs. 18A-D. Analysis of the cardiac transcriptome post-IR using RNA sequencing. (Fig. 18A) Principal component analysis (PCA) of the cardiac transcriptome of sham-treated mice (n=3) and mice subjected to ischemia/reperfusion (IR) injury with either no injection (n=3), injection of a control virus (n=3) or intracardiac injection of AAV-ABE- sgRNA6 (IR+Edit; n=4). (Fig. 18B) Heat map of the 211 differentially expressed genes between sham-treated mice and mice subjected to IR with injection of a control virus. (Fig. 18C) Gene ontology terms associated with the 163 genes upregulated in mice subjected to IR and a control virus. (Fig. 18D) Gene ontology terms associated with the 48 genes downregulated in mice subjected to IR and a control virus. Data are presented as individual data points. [0038] Fig. 19. Genomic editing of CaMKIIδ gene prevents myocardial fibrosis and infiltration of inflammatory cells post-IR. Transverse cross-sections of trichrome stained hearts for one sham-treated mouse and mice subjected to ischemia/reperfusion (IR) injury with either no injection, injection of a control virus or injection of AAV-ABE-sgRNA6 (IR+Edit; 10x magnification, scale bar 50 μm). [0039] Figs.20A-B. Decreased fibrosis in CaMKIIδ edited mice post-IR. (Fig.20A) Whole transverse cross-sections of picrosirius red stained hearts for one sham-treated mouse and mice subjected to ischemia/reperfusion (IR) injury with either no injection, injection of a control virus or injection of AAV-ABE-sgRNA6 (IR+Edit; scale bar 500 μm). (Fig.20B) Mean percentage of fibrotic cardiac tissue in each group. Replicates are individual mice. Statistical comparisons are based on one-way ANOVA post-hoc corrected by Holm-Sidak. Data are presented as individual data points with means ± SEM. [0040] Figs. 21A-I. Preserved exercise performance 260 days after systemic administration of AAV-ABE-sgRNA6. (Fig. 21A) Experimental design to investigate potential long-term adverse effects of CaMKIIδ gene editing. Mice were subjected to a treadmill exhaustion test 260 days after intraperitoneal administration of AAV-ABE-sgRNA6. After exhaustion, cardiac function was immediately assessed using echocardiography. (Fig. 21B) Mean bodyweight of CaMKIIδ edited mice (Edit) and their non-injected littermates (WT). (Fig.21C) Mean maximal velocity achieved on the treadmill for both groups. (Fig.21D) Mean distance attained on the treadmill prior to exhaustion for both groups. (Fig. 21E) Mean fractional shortening immediately after exhaustion. (Fig. 21F) Mean left ventricular end- diastolic posterior wall thickness. (Fig.21G) Mean left ventricular end-diastolic diameter. (Fig. 21H) Mean left ventricular end-diastolic volume. (Fig.21I) Mean heart rate. Replicates are five individual mice per group. Statistical comparisons are based on unpaired Student’s t tests. Data are presented as individual data points with means ± SEM. [0041] Fig.22 Mouse- CamKIIδ Gene and Protein Sequences (SEQ ID NOs: 96 & 97). [0042] Fig. 23 Human- CamKIIδ Gene and Protein Sequences (SEQ ID NOs: 98 & 99). DETAILED DESCRIPTION [0043] Despite current medical advancements, effective treatment for cardiovascular disease remains challenging. Up to now, precise gene editing technologies, such as BE and PE, are mainly considered as an innovative opportunity to correct hereditary mutations. However, these techniques could also be used to ablate deleterious pathways in disease settings. Here, using CRISPR-Cas9 Adenine-Base-Editing, the inventors developed an sgRNA that is able to ablate the oxidative activation site of CaMKIIδ. Following stress-editing, human stem-cell derived cardiomyocytes showed decreased CaMKII activity after oxidative stress and were protected from deleterious calcium dysregulation. They further applied stress-editing therapy to mice subjected to ischemia-reperfusion injury that perfectly corresponds to the clinical scenario of a myocardial infarction. The stress-editing system was delivered using an AAV9 split-virus by intracardiac injection, which is also possible in human patients. The inventors used a cardiac troponin promoter to ensure selectivity for the heart. Important, while injured mice showed markedly impaired cardiac function, stress-edited mice recovered from ischemia/reperfusion injury. Sequencing of isolated DNA and cDNA proved a successful ablation of the CaMKIIδ activation site. Significantly, this beneficial CaMKIIδ inhibition is permanent, provide a “one and done” approach. [0044] These and other aspects of the disclosure are set out in detail below. I. Cardiovascular Disease and Myocardial Infarction [0045] Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, abnormal heart rhythms, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis. [0046] The underlying mechanisms vary depending on the disease. It is estimated that dietary risk factors are associated with 53% of CVD deaths. Coronary artery disease, stroke, and peripheral artery disease involve atherosclerosis. This may be caused by high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, excessive alcohol consumption, and poor sleep, among other things. High blood pressure is estimated to account for approximately 13% of CVD deaths, while tobacco accounts for 9%, diabetes 6%, lack of exercise 6%, and obesity 5%. Rheumatic heart disease may follow untreated strep throat. [0047] Cardiovascular diseases are the leading cause of death worldwide except Africa. Deaths, at a given age, from CVD are more common and have been increasing in much of the developing world, while rates have declined in most of the developed world since the 1970s. Coronary artery disease and stroke account for 80% of CVD deaths in males and 75% of CVD deaths in females. Most cardiovascular disease affects older adults. In the United States 11% of people between 20 and 40 have CVD, while 37% between 40 and 60, 71% of people between 60 and 80, and 85% of people over 80 have CVD. [0048] Myocardial infarction (MI), commonly known as a heart attack, is a major cardiovascular insult that occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck or jaw. Often it occurs in the center or left side of the chest and lasts for more than a few minutes. The discomfort may occasionally feel like heartburn. Other symptoms may include shortness of breath, nausea, feeling faint, a cold sweat or feeling tired. About 30% of people have atypical symptoms. Women more often present without chest pain and instead have neck pain, arm pain or feel tired. Among those over 75 years old, about 5% have had an MI with little or no history of symptoms. An MI may cause heart failure, an irregular heartbeat, cardiogenic shock or cardiac arrest. [0049] Most MIs occur due to coronary artery disease. Risk factors include high blood pressure, smoking, diabetes, lack of exercise, obesity, high blood cholesterol, poor diet and excessive alcohol intake. The complete blockage of a coronary artery caused by a rupture of an atherosclerotic plaque is usually the underlying mechanism of an MI. MIs are less commonly caused by coronary artery spasms, which may be due to cocaine, significant emotional stress (commonly known as Takotsubo syndrome) and extreme cold, among others. A number of tests are useful to help with diagnosis, including electrocardiograms (ECGs), blood tests and coronary angiography. An ECG, which is a recording of the heart's electrical activity, may confirm an ST elevation MI (STEMI), if ST elevation is present. Commonly used blood tests include troponin and less often creatine kinase MB. [0050] Treatment of an MI is time-critical. Aspirin is an appropriate immediate treatment for a suspected MI. Nitroglycerin or opioids may be used to help with chest pain; however, they do not improve overall outcomes. Supplemental oxygen is recommended in those with low oxygen levels or shortness of breath. In a STEMI, treatments attempt to restore blood flow to the heart and include percutaneous coronary intervention (PCI), where the arteries are pushed open and may be stented, or thrombolysis, where the blockage is removed using medications. People who have a non-ST elevation myocardial infarction (NSTEMI) are often managed with the blood thinner heparin, with the additional use of PCI in those at high risk. In people with blockages of multiple coronary arteries and diabetes, coronary artery bypass surgery (CABG) may be recommended rather than angioplasty. After an MI, lifestyle modifications, along with long-term treatment with aspirin, beta blockers and statins, are typically recommended. [0051] Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue after a period of ischemia or lack of oxygen (anoxia or hypoxia). The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than (or along with) restoration of normal function. MI treatments that seek to restore blood flow to ischemic heart tissue can result in IRI and further damage. [0052] Worldwide, about 15.9 million myocardial infarctions occurred in 2015. More than 3 million people had an ST elevation MI, and more than 4 million had an NSTEMI. STEMIs occur about twice as often in men as women. About one million people have an MI each year in the United States. In the developed world, the risk of death in those who have had a STEMI is about 10%. Rates of MI for a given age have decreased globally between 1990 and 2010. In 2011, an MI was one of the top five most expensive conditions during inpatient hospitalizations in the US, with a cost of about $11.5 billion for 612,000 hospital stays. II. CaMKIIδ [0053] Ca ²⁺ /calmodulin-dependent protein kinase II (CaM kinase II or CaMKII) is a group of serine/threonine-specific protein kinases that are regulated by the Ca ²⁺ /calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory. CaMKII is also necessary for Ca ²⁺ homeostasis and reuptake in cardiomyocytes, chloride transport in epithelia, positive T-cell selection, and CD8 T-cell activation. Dysregulation of CaMKII is linked to Alzheimer's disease, Angelman syndrome, and heart arrhythmia. The four isoforms derive from the alpha, beta, gamma, and delta genes. [0054] All of the isoforms of CaMKII have: a catalytic domain, an autoinhibitory domain, a variable segment, and a self-association domain. The catalytic domain has several binding sites for ATP and other substrate anchor proteins. It is responsible for the transfer of phosphate from ATP to Ser or Thr residues in substrates. The autoinhibitory domain features a pseudosubstrate site, which binds to the catalytic domain and blocks its ability to phosphorylate proteins. [0055] The structural feature that governs autoinhibition is the Threonine 287 residue. Phosphorylation of this site will permanently activate the CaMKII enzyme. Once the Threonine 287 residue has been phosphorylated, the inhibitory domain is blocked from the pseudosubstrate site. This effectively blocks autoinhibition, allowing for permanent activation of the CaMKII enzyme. This enables CaMKII to be active, even in the absence of calcium and calmodulin. [0056] The other two domains in CaMKII are the variable and self-association domains. Differences in these domains contribute to the various CaMKII splicing isoforms. The self-association domain (CaMKII AD) is found at the C terminus, the function of this domain is the assembly of the single proteins into large (8 to 14 subunits) multimers. [0057] The sensitivity of the CaMKII enzyme to calcium and calmodulin is governed by the variable and self-associative domains. This sensitivity level of CaMKII will also modulate the different states of activation for the enzyme. Initially, the enzyme is activated; however, autophosphorylation does not occur because there is not enough calcium or calmodulin present to bind to neighboring subunits. As greater amounts of calcium and calmodulin accumulate, autophosphorylation occurs leading to persistent activation of the CaMKII enzyme for a short period of time. However, the Threonine 287 residue eventually becomes dephosphorylated, leading to inactivation of CaMKII. Besides Threonine 287, there are several other amino acids that can undergo posttranslational modification. Among them, Methionines 281 and 282 have been shown to get modified upon oxidative stress and to be critical for CaMKIIδ activation in disease. [0058] CaMKIIδ appears in both neuronal and non-neuronal cell types. It is characterized particularly in many tumor cells, such as a variety of pancreatic, leukemic, breast and other tumor cells. Several CaMKIIδ variants are highly abundant in myocardial tissue. Increased CaMKII activity has been observed in patients with heart failure, structural heart disease and arrhythmias and CaMKII inhibition has been shown to be beneficial for cardiac disease in preclinical settings. Even though multiple CaMKII inhibitors have already been developed, they all show several limitations, and no compound has been translated into the clinic. The inventors developed a new strategy to overcome the limitations of current CaMKII inhibitors, by precise modulation of CaMKIIδ oxidative activation sites using CRISPR/Cas9 base editing technology. III. CRISPR Systems [0059] Gene editing is a technology that allows for the modification of target genes within living cells. Recently, harnessing the bacterial immune system of CRISPR to perform on demand gene editing revolutionized the way scientists approach genomic editing. The Cas9 protein of the CRISPR system, which is an RNA guided DNA endonuclease, can be engineered to target new sites with relative ease by altering its guide RNA sequence. This discovery has made sequence specific gene editing functionally effective. [0060] In general, “CRISPR system” refers collectively to transcripts and other elements involved in the expression of or directing the activity of CRISPR-associated (“Cas”) genes, including sequences encoding a Cas gene, a tracr (trans-activating CRISPR) sequence (e.g., tracrRNA or an active partial tracrRNA), a tracr-mate sequence (encompassing a “direct repeat” and a tracrRNA-processed partial direct repeat in the context of an endogenous CRISPR system), a guide sequence (also referred to as a “spacer” in the context of an endogenous CRISPR system), and/or other sequences and transcripts from a CRISPR locus. [0061] The CRISPR/Cas nuclease or CRISPR/Cas nuclease system can include a non- coding RNA molecule (guide) RNA, which sequence-specifically binds to DNA, and a Cas protein (e.g., Cas9), with nuclease functionality (e.g., two nuclease domains). One or more elements of a CRISPR system can derive from a type I, type II, or type III CRISPR system, e.g., derived from a particular organism comprising an endogenous CRISPR system, such as Streptococcus pyogenes. [0062] The CRISPR system can induce double stranded breaks (DSBs) at the target site, followed by disruptions as discussed herein. In other embodiments, Cas9 variants, deemed “nickases,” are used to nick a single strand at the target site. Paired nickases can be used, e.g., to improve specificity, each directed by a pair of different sgRNAs targeting sequences such that upon introduction of the nicks simultaneously, a 5' overhang is introduced. In other embodiments, catalytically inactive Cas9 is fused to a heterologous effector domain such as a base editing enzyme or a reverse transcriptase. [0063] The engineered CRISPR technologies of base editing and prime editing have expanded the toolbox of gene editing strategies to potentially correct genetic mutations by enabling precise edits at individual nucleotides (Chemello et al., 2020). In base editing, Cas9 nickase (nCas9) or deactivated Cas9 (dCas9) is fused to a deaminase protein, allowing precise single-base pair conversions without DSBs within a defined editing window in relation to the protospacer adjacent motif (PAM) site of a sgRNA (Rees et al., 2018). There are two major classes of DNA base editors: cytosine base editors (CBEs), which convert a C:G base pair into a T:A base pair, and adenine base editors (ABEs), which convert an A:T base pair into a G:C base pair. As such, base editors allow efficient installation of single base substitutions in DNA. For example, adenosine deaminases induce adenosine (A) to inosine (I) edits in single-stranded DNA that in turn result in A-to-G transitions after DNA repair or replication. Adenine base editors (ABEs) are fusions of programmable DNA-binding domains (e.g., catalytically impaired RNA-guided CRISPR/Cas nucleases) linked to an engineered adenosine deaminase. In instances where the programmable DNA-binding domain is a CRISPR/Cas nuclease, targeted adenines lie within an “editing window” in the single-stranded (ss) DNA bubble (R- loop) induced by the CRISPR-Cas RNA-protein complex. The most commonly used ABEs comprise an adenosine deaminase heterodimer consisting of E. coli TadA (wild-type) fused to an engineered E. coli TadA variant (e.g., ABEmax) or a single engineered E. coli TadA variant (e.g., ABE8e, ABE8eV106W, or ABE8.20-m) as well as a nickase Cas9 and nuclear localization sequences (NLS). ABEs have been used successfully for installation of A-to-G substitutions in multiple cell types and organisms and could potentially reverse a large number of mutations known to be associated with human disease. Examples of ABEs include those described in U.S. Pat. Publn. US20200308571, PCT Publn. WO2020214842, and PCT Publn. WO2021025750, which are each incorporated herein by reference in their entirety. Reference is made to International Publication No. WO 2018/027078, published August 2, 2018; International Publication No. WO 2019/079347 published April 25, 2019; International Publication No. WO 2019/226593, published November 28, 2019; U.S. Patent Publication No. 2018/0073012, published March 15, 2018, which issued as U.S. Patent No. 10,113,163, on October 30, 2018; and U.S. Patent Publication No. 2017/0121693, published May 4, 2017, which issued as U.S. Patent No.10,167,457 on January 1, 2019. [0064] In some aspects, a Cas nuclease and sgRNA (including a fusion of crRNA specific for the target sequence and fixed tracrRNA) are introduced into the cell. In general, target sites at the 5' end of the sgRNA target the Cas nuclease to the target site, e.g., the gene, using complementary base pairing. Target sites may be 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10 nucleotides in length. The target site may be selected based on its location immediately 5' of a protospacer adjacent motif (PAM) sequence, such as typically NGG, NG, NRN, NYN, NAG, NNNRRT, or NNGG. In general, a CRISPR system is characterized by elements that promote the formation of a CRISPR complex at the site of a target sequence. Typically, “target sequence” generally refers to a sequence to which a guide sequence is designed to have complementarity, where hybridization between the target sequence and a guide sequence promotes the formation of a CRISPR complex. Full complementarity is not necessarily required, provided there is sufficient complementarity to cause hybridization and promote formation of a CRISPR complex. [0065] The target sequence may comprise any polynucleotide, such as DNA or RNA polynucleotides. The target sequence may be located in the nucleus or cytoplasm of the cell, such as within an organelle of the cell. Generally, a sequence or template that may be used for recombination into the targeted locus comprising the target sequences is referred to as an “editing template” or “editing polynucleotide” or “editing sequence.” In some aspects, an exogenous template polynucleotide may be referred to as an editing template. In some aspects, recombination is homologous recombination. [0066] Typically, in the context of an endogenous CRISPR system, formation of the CRISPR complex (comprising the guide sequence hybridized to the target sequence and complexed with one or more Cas proteins) results in cleavage of one or both strands in or near (e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from) the target sequence. The tracr sequence, which may comprise or consist of all or a portion of a wild-type tracr sequence (e.g., about or more than about 20, 26, 32, 45, 48, 54, 63, 67, 85, or more nucleotides of a wild-type tracr sequence), may also form part of the CRISPR complex, such as by hybridization along at least a portion of the tracr sequence to all or a portion of a tracr mate sequence that is operably linked to the guide sequence. The tracr sequence has sufficient complementarity to a tracr mate sequence to hybridize and participate in formation of the CRISPR complex, such as at least 50%, 60%, 70%, 80%, 90%, 95% or 99% of sequence complementarity along the length of the tracr mate sequence when optimally aligned. [0067] One or more vectors driving expression of one or more elements of the CRISPR system can be introduced into the cell such that expression of the elements of the CRISPR system direct formation of the CRISPR complex at one or more target sites. Components can also be delivered to cells as proteins and/or RNA. For example, a Cas enzyme, a guide sequence linked to a tracr-mate sequence, and a tracr sequence could each be operably linked to separate regulatory elements on separate vectors. The sgRNA may be under the control of a constitutive promoter. [0068] Alternatively, two or more of the elements expressed from the same or different regulatory elements may be combined in a single vector, with one or more additional vectors providing any components of the CRISPR system not included in the first vector. The vector may comprise one or more insertion sites, such as a restriction endonuclease recognition sequence (also referred to as a “cloning site”). In some embodiments, one or more insertion sites are located upstream and/or downstream of one or more sequence elements of one or more vectors. When multiple different guide sequences are used, a single expression construct may be used to target CRISPR activity to multiple different, corresponding target sequences within a cell. [0069] A vector may comprise a regulatory element operably linked to an enzyme- coding sequence encoding the CRISPR enzyme, such as a Cas protein. Non-limiting examples of Cas proteins include Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas9 (also known as Csn1 and Csx12), Cas10, Csy1, Csy2, Csy3, Cse1, Cse2, Csc1, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx15, Csfl, Csf2, Csf3, Csf4, homologs thereof, or modified versions thereof. These enzymes are known; for example, the amino acid sequence of S. pyogenes Cas9 protein may be found in the SwissProt database under accession number Q99ZW2. [0070] The CRISPR enzyme can be Cas9 (e.g., from S. pyogenes or S. pneumonia or S. aureus or S. auricularis or S. lugdunensis). The CRISPR enzyme can direct cleavage of one or both strands at the location of a target sequence, such as within the target sequence and/or within the complement of the target sequence. The vector can encode a CRISPR enzyme that is mutated with respect to a corresponding wild-type enzyme such that the mutated CRISPR enzyme lacks the ability to cleave one or both strands of a target polynucleotide containing a target sequence. For example, an aspartate-to-alanine substitution (D10A) in the RuvC I catalytic domain of Cas9 from S. pyogenes converts Cas9 from a nuclease that cleaves both strands to a nickase (cleaves a single strand). In some embodiments, a Cas9 nickase may be used in combination with guide sequence(s), e.g., two guide sequences, which target respectively sense and antisense strands of the DNA target. This combination allows both strands to be nicked and used to induce NHEJ or HDR. [0071] In some embodiments, a Cas9 polypeptide can be a deactivated (e.g., mutated, dCAs9) Cas9 polypeptide, wherein the deactivated Cas9 does not comprise HNH and/or RuvC nickase activities. The HNH and RuvC motifs have been characterized in S. thermophilus (see, e.g., Sapranauskas et al. Nucleic Acids Res. 39:9275-9282 (2011)) and one of skill would be able to identify and mutate these motifs in Cas9 polypeptides from other organisms. For example, the mutations D10A and H840A completely inactivate the nuclease activity of S. pyogenes Cas9. Notably, a Cas9 polypeptide in which the HNH motif and/or RuvC motif is/are specifically mutated so that the nickase activity is reduced, deactivated, and/or absent, can retain one or more of the other known Cas9 functions including DNA, RNA and PAM recognition and binding activities and thus remain functional with regard to these activities, while non-functional with regard to one or both nickase activities. [0072] In an alternative embodiment, the CRIPSR enzyme is a Cas protein, preferably Cas9 (having a nucleotide sequence of Genbank accession no NC_002737.2 and a protein sequence of Genbank accession no NP_269215.1). Again, the Cas9 protein may also be modified to improve activity. For example, the Cas9 protein may comprise the D10A amino acid substitution, this nickase cleaves only the DNA strand that is complementary to and recognized by the crRNA. In an alternative embodiment, the Cas9 protein may alternatively or additionally comprise the H840A amino acid substitution, this nickase cleaves only the DNA strand that does not interact with the sRNA. In this embodiment, Cas9 may be used with a pair (i.e. two) sgRNA molecules (or a construct expressing such a pair) and as a result can cleave the target region on the opposite DNA strand, with the possibility of improving specificity by 100-1500 fold. In a further embodiment, the Cas9 protein may comprise a D1135E substitution. The Cas 9 protein may also be the VQR, VRQR or SpRY variant. Alternatively, the Cas9 protein may be xCas9 (a Streptococcus pyogenes variant that can recognize a broad range of PAM sequences including NG, GAA and GAT). In other alternatives, the Cas9 variant is SpCas9-NG (with a relaxed preference to the third nucleotide of the PAM motif, such that the variant can recognize sequences where the PAM motif is NGN rather than NGG), SaCas9 (from S. aureus that can recognize NNGRR(T) PAM sequences; see Ran, F. A. et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature 520, 186-191, doi:10.1038/nature14299 (2015)), SaCas9-KKH (a variant from S. aureus that can recognize NNNRRT PAM sequences), SauCas9 (from S. auricularis that can recognize NNGG PAM sequences; Genbank accession no WP_107392933.1), or SlugCas9 (from S. lugdunensis M23590 that can recognize NNGG PAM sequences; Genbank accession no WP_002460848.1). [0073] In some embodiments, an enzyme coding sequence encoding the CRISPR enzyme is codon optimized for expression in particular cells, such as eukaryotic cells. The eukaryotic cells may be those of or derived from a particular organism, such as a mammal, including but not limited to human, mouse, rat, rabbit, dog, or non-human primate. In general, codon optimization refers to a process of modifying a nucleic acid sequence for enhanced expression in the host cells of interest by replacing at least one codon of the native sequence with codons that are more frequently or most frequently used in the genes of that host cell while maintaining the native amino acid sequence. Various species exhibit particular bias for certain codons of a particular amino acid. Codon bias (differences in codon usage between organisms) often correlates with the efficiency of translation of messenger RNA (mRNA), which is in turn believed to be dependent on, among other things, the properties of the codons being translated and the availability of particular transfer RNA (tRNA) molecules. The predominance of selected tRNAs in a cell is generally a reflection of the codons used most frequently in peptide synthesis. Accordingly, genes can be tailored for optimal gene expression in a given organism based on codon optimization. [0074] In general, a guide sequence is any polynucleotide sequence having sufficient complementarity with a target polynucleotide sequence to hybridize with the target sequence and direct sequence-specific binding of the CRISPR complex to the target sequence. In some embodiments, the degree of complementarity between a guide sequence and its corresponding target sequence, when optimally aligned using a suitable alignment algorithm, is about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, or more. [0075] Each of the guide sequences may further comprise additional nucleotides to form or encode a crRNA, e.g., using any known sequence appropriate for the Cas9 being used. In some embodiments, the crRNA comprises (5’ to 3’) at least a spacer sequence and a first complementarity domain. The first complementary domain is sufficiently complementary to a second complementarity domain, which may be part of the same molecule in the case of an sgRNA or in a tracrRNA in the case of a dual or modular sgRNA, to form a duplex. See, e.g., US 2017/0007679 for detailed discussion of crRNA and sgRNA domains, including first and second complementarity domains. [0076] A single-molecule guide RNA (sgRNA) can comprise, in the 5' to 3' direction, an optional spacer extension sequence, a spacer sequence, a minimum CRISPR repeat sequence, a single-molecule guide linker, a minimum tracrRNA sequence, a 3' tracrRNA sequence and/or an optional tracrRNA extension sequence. The optional tracrRNA extension can comprise elements that contribute additional functionality (e.g., stability) to the guide RNA. The single-molecule guide linker can link the minimum CRISPR repeat and the minimum tracrRNA sequence to form a hairpin structure. The optional tracrRNA extension can comprise one or more hairpins. In particular embodiments, the disclosure provides for an sgRNA comprising a spacer sequence and a tracrRNA sequence. [0077] The guide RNA can be considered to comprise a scaffold sequence necessary for endonuclease binding and a spacer sequence required to bind to the genomic target sequence. [0078] An exemplary scaffold sequence suitable for use with SaCas9 to follow the guide sequence at its 3’ end is: GTTTAAGTACTCTGTGCTGGAAACAGCACAGAATCTACTTAAACAAGGCAAAAT GCCGTGTTTATCTCGTCAACTTGTTGGCGAGA (SEQ ID NO: 95) in 5’ to 3’ orientation. In some embodiments, an exemplary scaffold sequence for use with SaCas9 to follow the 3’ end of the guide sequence is a sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 95, or a sequence that differs from SEQ ID NO: 95 by no more than 1, 2, 3, 4, 5, 10, 15, 20, or 25 nucleotides. [0079] Optimal alignment may be determined with the use of any suitable algorithm for aligning sequences, non-limiting example of which include the Smith-Waterman algorithm, the Needleman-Wunsch algorithm, algorithms based on the Burrows-Wheeler Transform (e.g., the Burrows Wheeler Aligner), Clustal W, Clustal X, BLAT, Novoalign (Novocraft Technologies, ELAND (Illumina, San Diego, Calif.), SOAP (available at soap.genomics.org.cn), and Maq (available at maq.sourceforge.net). [0080] The CRISPR enzyme may be part of a fusion protein comprising one or more heterologous protein domains. A CRISPR enzyme fusion protein may comprise any additional protein sequence, and optionally a linker sequence between any two domains. Examples of protein domains that may be fused to a CRISPR enzyme include, without limitation, epitope tags, reporter gene sequences, and protein domains having one or more of the following activities: methylase activity, demethylase activity, transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, RNA cleavage activity, nucleic acid binding activity, base editing activity, or reverse transcription activity. Non-limiting examples of epitope tags include histidine (His) tags, V5 tags, FLAG tags, influenza hemagglutinin (HA) tags, Myc tags, VSV-G tags, and thioredoxin (Trx) tags. Examples of reporter genes include, but are not limited to, glutathione-5- transferase (GST), horseradish peroxidase (HRP), chloramphenicol acetyltransferase (CAT) beta galactosidase, beta-glucuronidase, luciferase, green fluorescent protein (GFP), HcRed, DsRed, cyan fluorescent protein (CFP), yellow fluorescent protein (YFP), and autofluorescent proteins including blue fluorescent protein (BFP). A CRISPR enzyme may be fused to a gene sequence encoding a protein or a fragment of a protein that bind DNA molecules or bind other cellular molecules, including but not limited to maltose binding protein (MBP), S-tag, Lex A DNA binding domain (DBD) fusions, GAL4A DNA binding domain fusions, and herpes simplex virus (HSV) BP16 protein fusions. Additional domains that may form part of a fusion protein comprising a CRISPR enzyme are described in US 20110059502, incorporated herein by reference. [0081] As an RNA guided protein, Cas9 requires a short RNA to direct the recognition of DNA targets. Though Cas9 preferentially interrogates DNA sequences containing a PAM sequence (e.g., NGG or NG or NNNRRT or NNGG) it can bind here without a protospacer target. However, the Cas9-sgRNA complex requires a close match to the sgRNA to create a double strand break. CRISPR sequences in bacteria are expressed in multiple RNAs and then processed to create guide strands for RNA. Because eukaryotic systems lack some of the proteins required to process CRISPR RNAs, the synthetic construct sgRNA was created to combine the essential pieces of RNA for Cas9 targeting into a single RNA expressed with the RNA polymerase type III promoter U6. Other promoters under the control of RNA Pol III include those for ribosomal 5S rRNA, tRNA and few other small RNAs, RNase P and RNase MRP RNA, 7SL RNA (the RNA component of the signal recognition particles), Vault RNAs, Y RNA, SINEs (short interspersed repetitive elements), 7SK RNA, two microRNAs, several small nucleolar RNAs and several few regulatory antisense RNAs. Synthetic sgRNAs are slightly over 100 bp at the minimum length and contain a portion which targets the 20 or 21 protospacer nucleotides immediately preceding the PAM sequence. The length of the sgRNA can also be shortened at the 5’ with respect to its canonical length to meet specific criteria, e.g., the removal of a stretch of thymines that can inhibit the polymerase type III transcription activity. sgRNAs do not contain the PAM sequence. [0082] In some embodiments, the sgRNA targets a site within the CaMKIIδ gene. In some embodiments, the sgRNA targets a CaMKIIδ regulatory domain. In some embodiments, the sgRNA targets Met281 and/or Met282 of CaMKIIδ. [0083] In some embodiments, a nucleic acid may comprise one or more sequences encoding a sgRNA. In some embodiments, a nucleic acid may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 sequences encoding a sgRNA. In some embodiments, all of the sequences encode the same sgRNA. In some embodiments, all of the sequences encode different sgRNAs. In some embodiments, at least 2 of the sequences encode the same sgRNA, for example at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 of the sequences encode the same sgRNA. [0084] In some embodiments, nucleotide gene editing may be performed in vitro or ex vivo. In some embodiments, cells are contacted in vitro or ex vivo with a nucleotide editing Cas9 and a sgRNA that targets a CaMKIIδ site. In some embodiments, the cells are contacted with one or more nucleic acids encoding the Cas9 and the guide RNA. In some embodiments, the one or more nucleic acids are introduced into the cells using, for example, lipofection or electroporation. Nucleotide gene editing may also be performed in zygotes. In some embodiments, zygotes may be injected with one or more nucleic acids encoding Cas9 and a sgRNA that targets a CaMKIIδ site. The zygotes may subsequently be injected into a host. [0085] In some embodiments, the Cas9 is provided on a vector. In some embodiments, the vector contains a Cas9 derived from S. pyogenes (SpCas9). In some embodiments, the vector contains a Cas9 derived from S. aureus (SaCas9). In some embodiments, the vector contains a Cas9 derived from S. auricularis (SauCas9). In some embodiments, the vector contains a Cas9 derived from S. lugdunensis (SlugCas9). In some embodiments, the Cas9 sequence is codon optimized for expression in human cells or mouse cells. In some embodiments, the vector further contains a sequence encoding a fluorescent protein, such as GFP, which allows Cas 9-expressing cells to be sorted using fluorescence activated cell sorting (FACS). In some embodiments, the vector is a viral vector such as an adeno-associated viral vector. [0086] In some embodiments, the sgRNA is provided on a vector. In some embodiments, the vector is a viral vector such as an adeno-associated viral vector. In some embodiments, the Cas9 and the guide RNA are provided on the same vector. In some embodiments, the Cas9 and the guide RNA are provided on different vectors. [0087] Any type of vector, such as any of those described herein, may be used. In some embodiments, the vector is a lipid nanoparticle. In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is a non-integrating viral vector (i.e., that does not insert sequence from the vector into a host chromosome). In some embodiments, the viral vector is an adeno-associated virus vector (AAV), a lentiviral vector, an integrase-deficient lentiviral vector, an adenoviral vector, a vaccinia viral vector, an alphaviral vector, or a herpes simplex viral vector. In some embodiments, the vector comprises a cardiomyocyte-specific promoter. In some embodiments, the cardiomyocyte-specific promoter is a cardiac troponin T (cTnT) promoter. In any of the foregoing embodiments, the vector may be an adeno-associated virus vector (AAV). [0088] Where a vector is used, it may be a viral vector, such as a non-integrating viral vector. In some embodiments, the viral vector is an adeno-associated virus vector, a lentiviral vector, an integrase-deficient lentiviral vector, an adenoviral vector, a vaccinia viral vector, an alphaviral vector, or a herpes simplex viral vector. In some embodiments, the viral vector is an adeno-associated virus (AAV) vector. In some embodiments, the AAV vector is an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh10 (see, e.g., SEQ ID NO: 81 of U.S. Patent 9,790,472, which is incorporated by reference herein in its entirety), AAVrh74 (see, e.g., SEQ ID NO: 1 of U.S. Patent Publication No.2015/0111955, which is incorporated by reference herein in its entirety), AAV9 vector, AAV9P vector (also known as AAVMYO, see, Weinmann et al., 2020, Nature Communications, 11:5432), Myo-AAV vectors described in Tabebordbar et al., 2021, Cell, 184:1-20 (e.g., MyoAAV 1A, 2A, 3A, 4A, 4C, or 4E), and AAV9-rh74-HB-P1, AAV9-AAA-P1-SG vectors described in WO2022053630. wherein the number following AAV indicates the AAV serotype. In some embodiments, the AAV vector is a single-stranded AAV (ssAAV). In some embodiments, the AAV vector is a double- stranded AAV (dsAAV). Any variant of an AAV vector or serotype thereof, such as a self- complementary AAV (scAAV) vector, is encompassed within the general terms AAV vector, AAV1 vector, etc. See, e.g., McCarty et al., Gene Ther.2001; 8:1248–54, Naso et al., BioDrugs 2017; 31:317-334, and references cited therein for detailed discussion of various AAV vectors. In some embodiments, the vector is an AAV9 vector. [0089] Efficiency of in vitro or ex vivo nucleotide editing Cas9 may be assessed using techniques known to those of skill in the art, such as the T7 E1 assay or sequencing. [0090] In some embodiments, in vitro or ex vivo gene editing is performed in a cardiac cell. In some embodiments, gene editing is performed in iPSC or iCM cells. In some embodiments, the iPSC cells are differentiated after gene editing. For example, the iPSC cells may be differentiated into a cardiac cell after editing. In some embodiments, the iPSC cells are differentiated into cardiac muscle cells. In some embodiments, the iPSC cells are differentiated into cardiomyocytes. iPSC cells may be induced to differentiate according to methods known to those of skill in the art. [0091] In some embodiments, contacting the cell with the nucleotide editing Cas9 and the sgRNA prevents oxidative stress activation of CaMKIIδ. In some embodiments, the edited cells, or cells derived therefrom, show reduced or no level of CaMKIIδ activation as compared to non-edited cells. In other embodiments, gene editing is performed in wild-type mice/iPSC- CMs in response to cardiac injury (e.g., ischemia/reperfusion injury, transverse aortic constriction, etc.). IV. Nucleic Acid Delivery [0092] In some embodiments, expression cassettes are employed to express a protein product, either for subsequent purification and delivery to a cell/subject, or for use directly in a genetic-based delivery approach. Provided herein are expression vectors which contain one or more nucleic acids encoding nucleotide editing Cas9 and at least one guide RNA that targets a CaMKIIδ. In some embodiments, a nucleic acid encoding nucleotide editing Cas9 and a nucleic acid encoding at least one guide RNA are provided on the same vector. In further embodiments, a nucleic acid encoding nucleotide editing Cas9 and a nucleic acid encoding least one guide RNA are provided on separate vectors. [0093] Expression requires that appropriate signals be provided in the vectors and include various regulatory elements such as enhancers/promoters from both viral and mammalian sources that drive expression of the genes of interest in cells. Elements designed to optimize messenger RNA stability and translatability in host cells also are defined. The conditions for the use of a number of dominant drug selection markers for establishing permanent, stable cell clones expressing the products are also provided, as is an element that links expression of the drug selection markers to expression of the polypeptide. A. Regulatory Elements [0094] Throughout this application, the term “expression cassette” is meant to include any type of genetic construct containing a nucleic acid coding for a gene product in which part or all of the nucleic acid encoding sequence is capable of being transcribed and translated, i.e., is under the control of a promoter. A “promoter” refers to a DNA sequence recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a gene. The phrase “under transcriptional control” means that the promoter is in the correct location and orientation in relation to the nucleic acid to control RNA polymerase initiation and expression of the gene. An “expression vector” is meant to include expression cassettes comprised in a genetic construct that is capable of replication, and thus including one or more of origins of replication, transcription termination signals, poly-A regions, selectable markers, and multipurpose cloning sites. [0095] The term promoter will be used here to refer to a group of transcriptional control modules that are clustered around the initiation site for RNA polymerase II. Much of the thinking about how promoters are organized derives from analyses of several viral promoters, including those for the HSV thymidine kinase (tk) and SV40 early transcription units. These studies, augmented by more recent work, have shown that promoters are composed of discrete functional modules, each consisting of approximately 7-20 bp of DNA, and containing one or more recognition sites for transcriptional activator or repressor proteins. [0096] At least one module in each promoter functions to position the start site for RNA synthesis. The best-known example of this is the TATA box, but in some promoters lacking a TATA box, such as the promoter for the mammalian terminal deoxynucleotidyl transferase gene and the promoter for the SV40 late genes, a discrete element overlying the start site itself helps to fix the place of initiation. [0097] In some embodiments, the nucleotide editing Cas9 constructs of the disclosure are expressed by a muscle-cell specific promoter. This muscle-cell specific promoter may be constitutively active or may be an inducible promoter. [0098] Additional promoter elements regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have recently been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the tk promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. Depending on the promoter, it appears that individual elements can function either co-operatively or independently to activate transcription. [0099] In certain embodiments, viral promotes such as the human cytomegalovirus (CMV) immediate early gene promoter, the SV40 early promoter, the Rous sarcoma virus long terminal repeat, rat insulin promoter and glyceraldehyde-3-phosphate dehydrogenase can be used to obtain high-level expression of the coding sequence of interest. The use of other viral or mammalian cellular or bacterial phage promoters which are well-known in the art to achieve expression of a coding sequence of interest is contemplated as well, provided that the levels of expression are sufficient for a given purpose. By employing a promoter with well-known properties, the level and pattern of expression of the protein of interest following transfection or transformation can be optimized. Further, selection of a promoter that is regulated in response to specific physiologic signals can permit inducible expression of the gene product. [00100] Enhancers are genetic elements that increase transcription from a promoter located at a distant position on the same molecule of DNA. Enhancers are organized much like promoters. That is, they are composed of many individual elements, each of which binds to one or more transcriptional proteins. The basic distinction between enhancers and promoters is operational. An enhancer region as a whole must be able to stimulate transcription at a distance; this need not be true of a promoter region or its component elements. On the other hand, a promoter must have one or more elements that direct initiation of RNA synthesis at a particular site and in a particular orientation, whereas enhancers lack these specificities. Promoters and enhancers are often overlapping and contiguous, often seeming to have a very similar modular organization. [00101] Below is a list of promoters/enhancers and inducible promoters/enhancers that could be used in combination with the nucleic acid encoding a gene of interest in an expression construct. Additionally, any promoter/enhancer combination (as per the Eukaryotic Promoter Data Base EPDB) could also be used to drive expression of the gene. Eukaryotic cells can support cytoplasmic transcription from certain bacterial promoters if the appropriate bacterial polymerase is provided, either as part of the delivery complex or as an additional genetic expression construct. [00102] The promoter and/or enhancer may be, for example, immunoglobulin light chain, immunoglobulin heavy chain, T-cell receptor, HLA DQ a and/or DQ β, β-interferon, interleukin-2, interleukin-2 receptor, MHC class II 5, MHC class II HLA-Dra, β- Actin, muscle creatine kinase (MCK), prealbumin (transthyretin), elastase I, metallothionein (MTII), collagenase, albumin, α-fetoprotein, t-globin, β-globin, c-fos, c-HA-ras, insulin, neural cell adhesion molecule (NCAM), α ₁ -antitrypain, H2B (TH2B) histone, mouse and/or type I collagen, glucose-regulated proteins (GRP94 and GRP78), rat growth hormone, human serum amyloid A (SAA), troponin I (TN I), platelet-derived growth factor (PDGF), duchenne muscular dystrophy, SV40, polyoma, retroviruses, papilloma virus, hepatitis B virus, human immunodeficiency virus, cytomegalovirus (CMV), and gibbon ape leukemia virus. [00103] In some embodiments, inducible elements may be used. In some embodiments, the inducible element is, for example, MTII, MMTV (mouse mammary tumor virus), β-interferon, adenovirus 5 E2, collagenase, stromelysin, SV40, murine MX gene, GRP78 gene, α-2-macroglobulin, vimentin, MHC class I gene H-2κb, HSP70, proliferin, tumor necrosis factor, and/or thyroid stimulating hormone α gene. In some embodiments, the inducer is phorbol ester (TFA), heavy metals, glucocorticoids, poly(rI)x, poly(rc), ElA, phorbol ester (TPA), interferon, Newcastle Disease Virus, A23187, IL-6, serum, interferon, SV40 large T antigen, PMA, and/or thyroid hormone. Any of the inducible elements described herein may be used with any of the inducers described herein. [00104] Of particular interest are cardiomyocyte-specific promoters. In some embodiments, the cardiomyocyte-specific promoter is the cardiac troponin T (cTnT) promoter. [00105] Where a cDNA insert is employed, one will typically desire to include a polyadenylation signal to effect proper polyadenylation of the gene transcript. Any polyadenylation sequence may be employed such as human growth hormone and SV40 polyadenylation signals. Also contemplated as an element of the expression cassette is a terminator. These elements can serve to enhance message levels and to minimize read through from the cassette into other sequences. B. 2A Peptide [00106] In some embodiments, a 2A-like self-cleaving domain from the insect virus Thosea asigna (TaV 2A peptide) (EGRGSLLTCGDVEENPGP (SEQ ID NO: 1)) is used. These 2A-like domains have been shown to function across eukaryotes and cause cleavage of amino acids to occur co-translationally within the 2A-like peptide domain. Therefore, inclusion of TaV 2A peptide allows the expression of multiple proteins from a single mRNA transcript. Importantly, the domain of TaV when tested in eukaryotic systems has shown greater than 99% cleavage activity. Other acceptable 2A-like peptides include, but are not limited to, equine rhinitis A virus (ERAV) 2A peptide (QCTNYALLKLAGDVESNPGP (SEQ ID NO: 2)), porcine teschovirus-1 (PTV1) 2A peptide (ATNFSLLKQAGDVEENPGP (SEQ ID NO: 3)) and foot and mouth disease virus (FMDV) 2A peptide (PVKQLLNFDLLKLAGDVESNPGP (SEQ ID NO: 4)) or modified versions thereof. [00107] In some embodiments, the 2A peptide is used to express a reporter and a nucleotide editing Cas9 simultaneously. The reporter may be, for example, GFP or mCherry. [00108] Other self-cleaving peptides that may be used include but are not limited to nuclear inclusion protein a (Nia) protease, a P1 protease, a 3C protease, a L protease, a 3C- like protease, or modified versions thereof. C. Trans-splicing Inteins [00109] In some embodiments, trans-splicing inteins are used to permit the covalent splicing of the split nucleotide editing Cas9. Due to delivery size limitation, nucleotide editing Cas9 can be split in N- and C-terminal peptides. Each half of the split nucleotide editing Cas9 when linked to trans-splicing inteins reassemble after translation into a functional nucleotide editing Cas9 that retains similar editing efficiencies compared to its non-split, full- length equivalent. [00110] In some embodiments, the N- and C-terminal peptides of nucleotide editing Cas9 are fused to split DnaE intein halves from N. puntiforme (Npu). [00111] Other trans-splicing inteins that may be used include but are not limited to Sce VMA, Mtu RecA, Ssp DnaE. D. Delivery of Expression Vectors [00112] There are a number of ways in which expression vectors may be introduced into cells. In certain embodiments, the expression construct comprises a virus or engineered construct derived from a viral genome. The ability of certain viruses to enter cells via receptor-mediated endocytosis, to integrate into host cell genome and express viral genes stably and efficiently have made them attractive candidates for the transfer of foreign genes into mammalian cells. These have a relatively low capacity for foreign DNA sequences and have a restricted host spectrum. Furthermore, their oncogenic potential and cytopathic effects in permissive cells raise safety concerns. They can accommodate only up to 8 kB of foreign genetic material but can be readily introduced in a variety of cell lines and laboratory animals. [00113] One method for in vivo delivery involves the use of an adenovirus expression vector. “Adenovirus expression vector” is meant to include those constructs containing adenovirus sequences sufficient to (a) support packaging of the construct and (b) to express an antisense polynucleotide that has been cloned therein. In this context, expression does not require that the gene product be synthesized. [00114] The expression vector comprises a genetically engineered form of adenovirus. Knowledge of the genetic organization of adenovirus, a 36 kB, linear, double- stranded DNA virus, allows substitution of large pieces of adenoviral DNA with foreign sequences up to 7 kB. In contrast to retrovirus, the adenoviral infection of host cells does not result in chromosomal integration because adenoviral DNA can replicate in an episomal manner without potential genotoxicity. Also, adenoviruses are structurally stable, and no genome rearrangement has been detected after extensive amplification. Adenovirus can infect virtually all epithelial cells regardless of their cell cycle stage. So far, adenoviral infection appears to be linked only to mild disease such as acute respiratory disease in humans. [00115] Adenovirus is particularly suitable for use as a gene transfer vector because of its mid-sized genome, ease of manipulation, high titer, wide target cell range and high infectivity. Both ends of the viral genome contain 100-200 base pair inverted repeats (ITRs), which are cis elements necessary for viral DNA replication and packaging. The early (E) and late (L) regions of the genome contain different transcription units that are divided by the onset of viral DNA replication. The E1 region (E1A and E1B) encodes proteins responsible for the regulation of transcription of the viral genome and a few cellular genes. The expression of the E2 region (E2A and E2B) results in the synthesis of the proteins for viral DNA replication. These proteins are involved in DNA replication, late gene expression and host cell shut-off. The products of the late genes, including the majority of the viral capsid proteins, are expressed only after significant processing of a single primary transcript issued by the major late promoter (MLP). The MLP, (located at 16.8 m.u.) is particularly efficient during the late phase of infection, and all the mRNAs issued from this promoter possess a 5’-tripartite leader (TPL) sequence which makes them preferred mRNAs for translation. In one system, recombinant adenovirus is generated from homologous recombination between shuttle vector and provirus vector. Due to the possible recombination between two proviral vectors, wild- type adenovirus may be generated from this process. Therefore, it is critical to isolate a single clone of virus from an individual plaque and examine its genomic structure. [00116] Generation and propagation of the current adenovirus vectors, which are replication deficient, depend on a unique helper cell line, designated 293, which was transformed from human embryonic kidney cells by Ad5 DNA fragments and constitutively expresses E1 proteins. Since the E3 region is dispensable from the adenovirus genome, the current adenovirus vectors, with the help of 293 cells, carry foreign DNA in either the E1, the D3 or both regions. In nature, adenovirus can package approximately 105% of the wild-type genome, providing capacity for about 2 extra kb of DNA. Combined with the approximately 5.5 kb of DNA that is replaceable in the E1 and E3 regions, the maximum capacity of the current adenovirus vector is under 7.5 kb, or about 15% of the total length of the vector. More than 80% of the adenovirus viral genome remains in the vector backbone and is the source of vector-borne cytotoxicity. Also, the replication deficiency of the E1-deleted virus is incomplete. [00117] Helper cell lines may be derived from human cells such as human embryonic kidney cells, muscle cells, hematopoietic cells or other human embryonic mesenchymal or epithelial cells. Alternatively, the helper cells may be derived from the cells of other mammalian species that are permissive for human adenovirus. Such cells include, e.g., Vero cells or other monkey embryonic mesenchymal or epithelial cells. As stated above, the preferred helper cell line is 293. [00118] The adenoviruses of the disclosure are replication defective, or at least conditionally replication defective. The adenovirus may be of any of the 42 different known serotypes or subgroups A-F. Adenovirus type 5 of subgroup C is the preferred starting material in order to obtain the conditional replication-defective adenovirus vector for use in the present disclosure. [00119] Retroviruses are a group of single-stranded RNA viruses characterized by an ability to convert their RNA to double-stranded DNA in infected cells by a process of reverse-transcription. The resulting DNA then stably integrates into cellular chromosomes as a provirus and directs synthesis of viral proteins. The integration results in the retention of the viral gene sequences in the recipient cell and its descendants. The retroviral genome contains three genes, gag, pol, and env that code for capsid proteins, polymerase enzyme, and envelope components, respectively. A sequence found upstream from the gag gene contains a signal for packaging of the genome into virions. Two long terminal repeat (LTR) sequences are present at the 5’ and 3’ ends of the viral genome. These contain strong promoter and enhancer sequences and are also required for integration in the host cell genome. [00120] In order to construct a retroviral vector, a nucleic acid encoding a gene of interest is inserted into the viral genome in the place of certain viral sequences to produce a virus that is replication defective. In order to produce virions, a packaging cell line containing the gag, pol, and env genes but without the LTR and packaging components is constructed. When a recombinant plasmid containing a cDNA, together with the retroviral LTR and packaging sequences is introduced into this cell line (by calcium phosphate precipitation for example), the packaging sequence allows the RNA transcript of the recombinant plasmid to be packaged into viral particles, which are then secreted into the culture media. The media containing the recombinant retroviruses is then collected, optionally concentrated, and used for gene transfer. Retroviral vectors are able to infect a broad variety of cell types. However, integration and stable expression require the division of host cells. [00121] There are certain limitations to the use of retrovirus vectors in all aspects of the present disclosure. For example, retrovirus vectors usually integrate into random sites in the cell genome. This can lead to insertional mutagenesis through the interruption of host genes or through the insertion of viral regulatory sequences that can interfere with the function of flanking genes. Another concern with the use of defective retrovirus vectors is the potential appearance of wild-type replication-competent virus in the packaging cells. This can result from recombination events in which the intact- sequence from the recombinant virus inserts upstream from the gag, pol, env sequence integrated in the host cell genome. However, new packaging cell lines are now available that should greatly decrease the likelihood of recombination. [00122] Other viral vectors may be employed as expression constructs in the present disclosure. Vectors derived from viruses such as vaccinia virus, adeno-associated virus (AAV) and herpesviruses may be employed. They offer several attractive features for various mammalian cells. [00123] In embodiments, particular embodiments, the vector is an AAV vector. AAV is a small virus that infects humans and some other primate species. AAV is not currently known to cause disease. The virus causes a very mild immune response, lending further support to its apparent lack of pathogenicity. In many cases, AAV vectors integrate into the host cell genome, which can be important for certain applications, but can also have unwanted consequences. Gene therapy vectors using AAV can infect both dividing and quiescent cells and persist in an extrachromosomal state without integrating into the genome of the host cell, although in the native virus some integration of virally carried genes into the host genome does occur. These features make AAV a very attractive candidate for creating viral vectors for gene therapy, and for the creation of isogenic human disease models. Recent human clinical trials using AAV for gene therapy in the retina have shown promise. AAV belongs to the genus Dependoparvovirus, which in turn belongs to the family Parvoviridae. The virus is a small (20 nm) replication-defective, non-enveloped virus. [00124] Wild-type AAV has attracted considerable interest from gene therapy researchers due to a number of features. Chief amongst these is the virus's apparent lack of pathogenicity. It can also infect non-dividing cells and has the ability to stably integrate into the host cell genome at a specific site (designated AAVS1) in the human chromosome 19. This feature makes it somewhat more predictable than retroviruses, which present the threat of a random insertion and of mutagenesis, which is sometimes followed by development of cancer. The AAV genome integrates most frequently into the site mentioned, while random incorporations into the genome take place with a negligible frequency. Development of AAVs as gene therapy vectors, however, has eliminated this integrative capacity by removal of the rep and cap from the DNA of the vector. The desired gene together with a promoter to drive transcription of the gene is inserted between the inverted terminal repeats (ITR) that aid in concatemer formation in the nucleus after the single-stranded vector DNA is converted by host cell DNA polymerase complexes into double-stranded DNA. AAV-based gene therapy vectors form episomal concatemers in the host cell nucleus. In non-dividing cells, these concatemers remain intact for the life of the host cell. In dividing cells, AAV DNA is lost through cell division, since the episomal DNA is not replicated along with the host cell DNA. Random integration of AAV DNA into the host genome is detectable but occurs at very low frequency. AAVs also present very low immunogenicity, seemingly restricted to generation of neutralizing antibodies, while they induce no clearly defined cytotoxic response. This feature, along with the ability to infect quiescent cells present their dominance over adenoviruses as vectors for human gene therapy. [00125] Use of the AAV does present some disadvantages. The cloning capacity of the vector is relatively limited and most therapeutic genes require the complete replacement of the virus's 4.8 kilobase genome. Large genes are, therefore, not suitable for use in a standard AAV vector. Options are currently being explored to overcome the limited coding capacity. The AAV ITRs of two genomes can anneal to form head to tail concatemers, almost doubling the capacity of the vector. Insertion of splice sites allows for the removal of the ITRs from the transcript. [00126] Because of AAV’s specialized gene therapy advantages, researchers have created an altered version of AAV termed self-complementary adeno-associated virus (scAAV). Whereas AAV packages a single strand of DNA and must wait for its second strand to be synthesized, scAAV packages two shorter strands that are complementary to each other. By avoiding second-strand synthesis, scAAV can express more quickly, although as a caveat, scAAV can only encode half of the already limited capacity of AAV. Recent reports suggest that scAAV vectors are more immunogenic than single stranded adenovirus vectors, inducing a stronger activation of cytotoxic T lymphocytes. [00127] The humoral immunity instigated by infection with the wild type is thought to be a very common event. The associated neutralizing activity limits the usefulness of the most commonly used serotype AAV2 in certain applications. Accordingly, the majority of clinical trials currently under way involve delivery of AAV2 into the brain, a relatively immunologically privileged organ. In the brain, AAV2 is strongly neuron specific. [00128] The AAV genome is built of single-stranded deoxyribonucleic acid (ssDNA), either positive- or negative-sensed, which is about 4.7 kilobase long. The genome comprises inverted terminal repeats (ITRs) at both ends of the DNA strand, and two open reading frames (ORFs): rep and cap. The former is composed of four overlapping genes encoding Rep proteins required for the AAV life cycle, and the latter contains overlapping nucleotide sequences of capsid proteins: VP1, VP2 and VP3, which interact together to form a capsid of an icosahedral symmetry. [00129] The Inverted Terminal Repeat (ITR) sequences comprise 145 bases each. They were named so because of their symmetry, which was shown to be required for efficient multiplication of the AAV genome. The feature of these sequences that gives them this property is their ability to form a hairpin, which contributes to so-called self-priming that allows primase-independent synthesis of the second DNA strand. The ITRs were also shown to be required for both integration of the AAV DNA into the host cell genome (19th chromosome in humans) and rescue from it, as well as for efficient encapsidation of the AAV DNA combined with generation of a fully assembled, deoxyribonuclease-resistant AAV particles. [00130] With regard to gene therapy, ITRs seem to be the only sequences required in cis next to the therapeutic gene: structural (cap) and packaging (rep) proteins can be delivered in trans. With this assumption many methods were established for efficient production of recombinant AAV (rAAV) vectors containing a reporter or therapeutic gene. However, it was also published that the ITRs are not the only elements required in cis for the effective replication and encapsidation. A few research groups have identified a sequence designated cis-acting Rep-dependent element (CARE) inside the coding sequence of the rep gene. CARE was shown to augment the replication and encapsidation when present in cis. [00131] On the “left side” of the genome there are two promoters called p5 and p19, from which two overlapping messenger ribonucleic acids (mRNAs) of different length can be produced. Each of these contains an intron which can be either spliced out or not. Given these possibilities, four various mRNAs, and consequently four various Rep proteins with overlapping sequence can be synthesized. Their names depict their sizes in kilodaltons (kDa): Rep78, Rep68, Rep52 and Rep40. Rep78 and 68 can specifically bind the hairpin formed by the ITR in the self-priming act and cleave at a specific region, designated terminal resolution site, within the hairpin. They were also shown to be necessary for the AAVS1-specific integration of the AAV genome. All four Rep proteins were shown to bind ATP and to possess helicase activity. It was also shown that they upregulate the transcription from the p40 promoter (mentioned below) but downregulate both p5 and p19 promoters. [00132] The right side of a positive-sensed AAV genome encodes overlapping sequences of three capsid proteins, VP1, VP2 and VP3, which start from one promoter, designated p40. The molecular weights of these proteins are 87, 72 and 62 kiloDaltons, respectively. The AAV capsid is composed of a mixture of VP1, VP2, and VP3 totaling 60 monomers arranged in icosahedral symmetry in a ratio of 1:1:10, with an estimated size of 3.9 MegaDaltons. [00133] The cap gene produces an additional, non-structural protein called the Assembly-Activating Protein (AAP). This protein is produced from ORF2 and is essential for the capsid-assembly process. The exact function of this protein in the assembly process and its structure have not been solved to date. [00134] All three VPs are translated from one mRNA. After this mRNA is synthesized, it can be spliced in two different manners: either a longer or shorter intron can be excised resulting in the formation of two pools of mRNAs: a 2.3 kb- and a 2.6 kb-long mRNA pool. Usually, especially in the presence of adenovirus, the longer intron is preferred, so the 2.3-kb-long mRNA represents the so-called “major splice”. In this form the first AUG codon, from which the synthesis of VP1 protein starts, is cut out, resulting in a reduced overall level of VP1 protein synthesis. The first AUG codon that remains in the major splice is the initiation codon for VP3 protein. However, upstream of that codon in the same open reading frame lies an ACG sequence (encoding threonine) which is surrounded by an optimal Kozak context. This contributes to a low level of synthesis of VP2 protein, which is actually VP3 protein with additional N terminal residues, as is VP1. [00135] Since the bigger intron is preferred to be spliced out, and since in the major splice the ACG codon is a much weaker translation initiation signal, the ratio at which the AAV structural proteins are synthesized in vivo is about 1:1:20, which is the same as in the mature virus particle. The unique fragment at the N terminus of VP1 protein was shown to possess the phospholipase A2 (PLA2) activity, which is probably required for the releasing of AAV particles from late endosomes. Muralidhar et al. reported that VP2 and VP3 are crucial for correct virion assembly. More recently, however, Warrington et al. showed VP2 to be unnecessary for the complete virus particle formation and an efficient infectivity, and also presented that VP2 can tolerate large insertions in its N terminus, while VP1 cannot, probably because of the PLA2 domain presence. [00136] The AAV vector may be replication-defective or conditionally replication defective. In some embodiments, the AAV vector is a recombinant AAV vector. In some embodiments, the AAV vector comprises a sequence isolated or derived from an AAV vector of serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 or any combination thereof. [00137] In some embodiments, a single viral vector is used to deliver a nucleic acid encoding a nucleotide editing Cas9 and at least one sgRNA to a cell. In some embodiments, nucleotide editing Cas9 is provided to a cell using a first viral vector and at least one sgRNA is provided to the cell using a second viral vector. In some embodiment, the nucleotide editing Cas9 may use a split-intein dual AAV system which reconstitutes the full- length nucleotide editor by protein trans-splicing. In these systems, the Cas9 protein or the base editor is split into two sections, each fused with one part of an intein system (e.g., intein-N and intein-C encoded by dnaEn and dnaEc, respectively). Upon co-expression, the two sections of the Cas9 protein or nucleobase editor are ligated together via intein-mediated protein splicing. See, U.S. Pat. Pub. US20180127780, which is incorporated by reference herein in its entirety. [00138] In some embodiments, a single viral vector is used to deliver a nucleic acid encoding nucleotide editing Cas9 and at least one sgRNA to a cell. In some embodiments, nucleotide editing Cas9 is provided to a cell using a first viral vector and at least one sgRNA is provided to the cell using a second viral vector. In some embodiment, the nucleotide editing Cas9 may use a split-intein dual AAV system which reconstitutes the full-length nucleotide editor by protein trans-splicing. In order to effect expression of sense or antisense gene constructs, the expression construct must be delivered into a cell. The cell may be a muscle cell, a satellite cell, a mesangioblast, a bone marrow derived cell, a stromal cell or a mesenchymal stem cell. In some embodiments, the cell is a cardiac muscle cell, a skeletal muscle cell, or a smooth muscle cell. In some embodiments, the cell is a cell in the tibialis anterior, quadriceps, soleus, triceps, extensor digitorum longus, diaphragm, or heart. In some embodiments, the cell is an induced pluripotent stem cell (iPSC) or inner cell mass cell (iCM). In further embodiments, the cell is a human iPSC or a human iCM. In some embodiments, human iPSCs or human iCMs of the disclosure may be derived from a cultured stem cell line, an adult stem cell, a placental stem cell, or from another source of adult or embryonic stem cells that does not require the destruction of a human embryo. Delivery to a cell may be accomplished in vitro, as in laboratory procedures for transforming cells lines, or in vivo or ex vivo, as in the treatment of certain disease states. One mechanism for delivery is via viral infection where the expression construct is encapsidated in an infectious viral particle. [00139] Several non-viral methods for the transfer of expression constructs into cultured mammalian cells also are contemplated by the present disclosure. These include calcium phosphate precipitation, DEAE-dextran, electroporation, via nanoparticles, direct microinjection, DNA-loaded liposomes and lipofectamine-DNA complexes, cell sonication, gene bombardment using high velocity microprojectiles, and receptor-mediated transfection. Some of these techniques may be successfully adapted for in vivo or ex vivo use. [00140] Once the expression construct has been delivered into the cell the nucleic acid encoding the gene of interest may be positioned and expressed at different sites. In certain embodiments, the nucleic acid encoding the gene may be stably integrated into the genome of the cell. This integration may be in the cognate location and orientation via homologous recombination (gene replacement), or it may be integrated in a random, non-specific location (gene augmentation). In yet further embodiments, the nucleic acid may be stably maintained in the cell as a separate, episomal segment of DNA. Such nucleic acid segments or “episomes” encode sequences sufficient to permit maintenance and replication independent of or in synchronization with the host cell cycle. How the expression construct is delivered to a cell and where in the cell the nucleic acid remains is dependent on the type of expression construct employed. [00141] In yet another embodiment, the expression construct may simply consist of naked recombinant DNA or plasmids. Transfer of the construct may be performed by any of the methods mentioned above which physically or chemically permeabilize the cell membrane. This is particularly applicable for transfer in vitro but it may be applied to in vivo use as well. DNA encoding a gene of interest may also be transferred in a similar manner in vivo and express the gene product. [00142] In still another embodiment for transferring a naked DNA expression construct into cells may involve particle bombardment. This method depends on the ability to accelerate DNA-coated microprojectiles to a high velocity allowing them to pierce cell membranes and enter cells without killing them. Several devices for accelerating small particles have been developed. One such device relies on a high voltage discharge to generate an electrical current, which in turn provides the motive force. The microprojectiles used have consisted of biologically inert substances such as tungsten or gold beads. [00143] In some embodiments, the expression construct is delivered directly to the liver, skin, and/or muscle tissue of a subject. This may require surgical exposure of the tissue or cells, to eliminate any intervening tissue between the gun and the target organ, i.e., ex vivo treatment. Again, DNA encoding a particular gene may be delivered via this method and still be incorporated by the present disclosure. [00144] In a further embodiment, the expression construct may be entrapped in a liposome. Liposomes are vesicular structures characterized by a phospholipid bilayer membrane and an inner aqueous medium. Multilamellar liposomes have multiple lipid layers separated by aqueous medium. They form spontaneously when phospholipids are suspended in an excess of aqueous solution. The lipid components undergo self-rearrangement before the formation of closed structures and entrap water and dissolved solutes between the lipid bilayers. Also contemplated are lipofectamine-DNA complexes. [00145] Liposome-mediated nucleic acid delivery and expression of foreign DNA in vitro has been very successful. A reagent known as Lipofectamine 2000 ^TM is widely used and commercially available. [00146] In certain embodiments, the liposome may be complexed with a hemagglutinating virus (HVJ) to facilitate fusion with the cell membrane and promote cell entry of liposome-encapsulated DNA. In other embodiments, the liposome may be complexed or employed in conjunction with nuclear non-histone chromosomal proteins (HMG-1). In yet further embodiments, the liposome may be complexed or employed in conjunction with both HVJ and HMG-1. In that such expression constructs have been successfully employed in transfer and expression of nucleic acid in vitro and in vivo, then they are applicable for the present disclosure. Where a bacterial promoter is employed in the DNA construct, it also will be desirable to include within the liposome an appropriate bacterial polymerase. [00147] Other expression constructs which can be employed to deliver a nucleic acid encoding a particular gene into cells are receptor-mediated delivery vehicles. These take advantage of the selective uptake of macromolecules by receptor-mediated endocytosis in almost all eukaryotic cells. Because of the cell type-specific distribution of various receptors, the delivery can be highly specific. [00148] Receptor-mediated gene targeting vehicles generally consist of two components: a cell receptor-specific ligand and a DNA-binding agent. Several ligands have been used for receptor-mediated gene transfer. The most extensively characterized ligands are asialoorosomucoid (ASOR) and transferrin. A synthetic neoglycoprotein, which recognizes the same receptor as ASOR, has been used as a gene delivery vehicle and epidermal growth factor (EGF) has also been used to deliver genes to squamous carcinoma cells. E. AAV-Cas9 vectors [00149] In some embodiments, a Cas9 base editor may be packaged into an AAV vector. In some embodiments, the AAV vector is a wild-type AAV vector. In some embodiments, the AAV vector contains one or more mutations. In some embodiments, the AAV vector is isolated or derived from an AAV vector of serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 or any combination thereof. [00150] Exemplary AAV-Cas9 vectors contain two ITR (inverted terminal repeat) sequences which flank a central sequence region comprising the Cas9 sequence. In some embodiments, the ITRs are isolated or derived from an AAV vector of serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 or any combination thereof. In some embodiments, the ITRs comprise or consist of full-length and/or wild-type sequences for an AAV serotype. In some embodiments, the ITRs comprise or consist of truncated sequences for an AAV serotype. In some embodiments, the ITRs comprise or consist of elongated sequences for an AAV serotype. In some embodiments, the ITRs comprise or consist of sequences comprising a sequence variation compared to a wild-type sequence for the same AAV serotype. In some embodiments, the sequence variation comprises one or more of a substitution, deletion, insertion, inversion, or transposition. In some embodiments, the ITRs comprise or consist of at least 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150 base pairs. In some embodiments, the ITRs comprise or consist of 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150 base pairs. In some embodiments, the ITRs have a length of 110 ± 10 base pairs. In some embodiments, the ITRs have a length of 120 ± 10 base pairs. In some embodiments, the ITRs have a length of 130 ± 10 base pairs. In some embodiments, the ITRs have a length of 140 ± 10 base pairs. In some embodiments, the ITRs have a length of 150 ± 10 base pairs. In some embodiments, the ITRs have a length of 115, 145, or 141 base pairs. [00151] In some embodiments, the AAV-Cas9 vector may contain one or more nuclear localization signals (NLS). In some embodiments, the AAV-Cas9 vector contains 1, 2, 3, 4, or 5 nuclear localization signals. Exemplary NLS include the c-myc NLS, the SV40 NLS, the hnRNPAI M9 NLS, the nucleoplasmin NLS, the sequence RMRKFKNKGKDTAELRRRRVEVSVELRKAKKDEQILKRRNV (SEQ ID NO: 5) of the IBB domain from importin-alpha, the sequences VSRKRPRP (SEQ ID NO: 6) and PPKKARED (SEQ ID NO: 7) of the myoma T protein, the sequence PQPKKKPL (SEQ ID NO: 8) of human p53, the sequence SALIKKKKKMAP (SEQ ID NO: 9) of mouse c-abl IV, the sequences DRLRR (SEQ ID NO: 10) and PKQKKRK (SEQ ID NO: 11) of the influenza virus NS1, the sequence RKLKKKIKKL (SEQ ID NO: 12) of the Hepatitis virus delta antigen and the sequence REKKKFLKRR (SEQ ID NO: 13) of the mouse Mx1 protein. Further acceptable nuclear localization signals include bipartite nuclear localization sequences such as the sequence KRKGDEVDGVDEVAKKKSKK (SEQ ID NO: 14) of the human poly(ADP- ribose) polymerase or the sequence RKCLQAGMNLEARKTKK (SEQ ID NO: 15) of the steroid hormone receptors (human) glucocorticoid. [00152] In some embodiments, the AAV-Cas9 vector may comprise additional elements to facilitate packaging of the vector and expression of the Cas9. In some embodiments, the AAV-Cas9 vector may comprise a polyA sequence. In some embodiments, the polyA sequence may be a mini-polyA sequence. In some embodiments, the AAV-CAs9 vector may comprise a transposable element. In some embodiments, the AAV-Cas9 vector may comprise a regulator element. In some embodiments, the regulator element is an activator or a repressor. [00153] In some embodiments, the AAV-Cas9 may contain one or more promoters. In some embodiments, the one or more promoters drive expression of the Cas9. In some embodiments, the one or more promoters are cardiomyocyte-specific promoters. Exemplary cardiac-specific promoters include the cardiac troponin T promoter and α-myosin heavy chain promoter. [00154] In some embodiments, the AAV-Cas9 vector may be optimized for production in yeast, bacteria, insect cells, or mammalian cells. In some embodiments, the AAV-Cas9 vector may be optimized for expression in human cells. In some embodiments, the AAV-Cas9 vector may be optimized for expression in a bacculovirus expression system. [00155] In some embodiments of the gene editing constructs of the disclosure, the construct comprises or consists of a promoter and a nuclease. In some embodiments, the construct comprises or consists of an cTnT promoter and a Cas9 nuclease. In some embodiments, the construct comprises or consists of an cTnT promoter and a Cas9 nuclease isolated or derived from Staphylococcus pyogenes (“SpCas9”). In some embodiments, the SpCas9 nuclease comprises or consists of a nucleotide sequence at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to GACAAGAAGTACAGCATCGGCCTGGACATCGGCACCAACTCTGTGGGCTGGGCCGTGATC AC CGACGAGTACAAGGTGCCCAGCAAGAAATTCAAGGTGCTGGGCAACACCGACCGGCACAG CA TCAAGAAGAACCTGATCGGAGCCCTGCTGTTCGACAGCGGCGAAACAGCCGAGGCCACCC GG CTGAAGAGAACCGCCAGAAGAAGATACACCAGACGGAAGAACCGGATCTGCTATCTGCAA GA GATCTTCAGCAACGAGATGGCCAAGGTGGACGACAGCTTCTTCCACAGACTGGAAGAGTC CT TCCTGGTGGAAGAGGATAAGAAGCACGAGCGGCACCCCATCTTCGGCAACATCGTGGACG AG GTGGCCTACCACGAGAAGTACCCCACCATCTACCACCTGAGAAAGAAACTGGTGGACAGC AC CGACAAGGCCGACCTGCGGCTGATCTATCTGGCCCTGGCCCACATGATCAAGTTCCGGGG CC ACTTCCTGATCGAGGGCGACCTGAACCCCGACAACAGCGACGTGGACAAGCTGTTCATCC AG CTGGTGCAGACCTACAACCAGCTGTTCGAGGAAAACCCCATCAACGCCAGCGGCGTGGAC GC CAAGGCCATCCTGTCTGCCAGACTGAGCAAGAGCAGACGGCTGGAAAATCTGATCGCCCA GC TGCCCGGCGAGAAGAAGAATGGCCTGTTCGGCAACCTGATTGCCCTGAGCCTGGGCCTGA CC CCCAACTTCAAGAGCAACTTCGACCTGGCCGAGGATGCCAAACTGCAGCTGAGCAAGGAC AC CTACGACGACGACCTGGACAACCTGCTGGCCCAGATCGGCGACCAGTACGCCGACCTGTT TC TGGCCGCCAAGAACCTGTCCGACGCCATCCTGCTGAGCGACATCCTGAGAGTGAACACCG AG ATCACCAAGGCCCCCCTGAGCGCCTCTATGATCAAGAGATACGACGAGCACCACCAGGAC CT GACCCTGCTGAAAGCTCTCGTGCGGCAGCAGCTGCCTGAGAAGTACAAAGAGATTTTCTT CG ACCAGAGCAAGAACGGCTACGCCGGCTACATTGACGGCGGAGCCAGCCAGGAAGAGTTCT AC AAGTTCATCAAGCCCATCCTGGAAAAGATGGACGGCACCGAGGAACTGCTCGTGAAGCTG AA CAGAGAGGACCTGCTGCGGAAGCAGCGGACCTTCGACAACGGCAGCATCCCCCACCAGAT CC ACCTGGGAGAGCTGCACGCCATTCTGCGGCGGCAGGAAGATTTTTACCCATTCCTGAAGG AC AACCGGGAAAAGATCGAGAAGATCCTGACCTTCCGCATCCCCTACTACGTGGGCCCTCTG GC CAGGGGAAACAGCAGATTCGCCTGGATGACCAGAAAGAGCGAGGAAACCATCACCCCCTG GA ACTTCGAGGAAGTGGTGGACAAGGGCGCTTCCGCCCAGAGCTTCATCGAGCGGATGACCA AC TTCGATAAGAACCTGCCCAACGAGAAGGTGCTGCCCAAGCACAGCCTGCTGTACGAGTAC TT CACCGTGTATAACGAGCTGACCAAAGTGAAATACGTGACCGAGGGAATGAGAAAGCCCGC CT TCCTGAGCGGCGAGCAGAAAAAGGCCATCGTGGACCTGCTGTTCAAGACCAACCGGAAAG TG ACCGTGAAGCAGCTGAAAGAGGACTACTTCAAGAAAATCGAGTGCTTCGACTCCGTGGAA AT CTCCGGCGTGGAAGATCGGTTCAACGCCTCCCTGGGCACATACCACGATCTGCTGAAAAT TA TCAAGGACAAGGACTTCCTGGACAATGAGGAAAACGAGGACATTCTGGAAGATATCGTGC TG ACCCTGACACTGTTTGAGGACAGAGAGATGATCGAGGAACGGCTGAAAACCTATGCCCAC CT GTTCGACGACAAAGTGATGAAGCAGCTGAAGCGGCGGAGATACACCGGCTGGGGCAGGCT GA GCCGGAAGCTGATCAACGGCATCCGGGACAAGCAGTCCGGCAAGACAATCCTGGATTTCC TG AAGTCCGACGGCTTCGCCAACAGAAACTTCATGCAGCTGATCCACGACGACAGCCTGACC TT TAAAGAGGACATCCAGAAAGCCCAGGTGTCCGGCCAGGGCGATAGCCTGCACGAGCACAT TG CCAATCTGGCCGGCAGCCCCGCCATTAAGAAGGGCATCCTGCAGACAGTGAAGGTGGTGG AC GAGCTCGTGAAAGTGATGGGCCGGCACAAGCCCGAGAACATCGTGATCGAAATGGCCAGA GA GAACCAGACCACCCAGAAGGGACAGAAGAACAGCCGCGAGAGAATGAAGCGGATCGAAGA GG GCATCAAAGAGCTGGGCAGCCAGATCCTGAAAGAACACCCCGTGGAAAACACCCAGCTGC AG AACGAGAAGCTGTACCTGTACTACCTGCAGAATGGGCGGGATATGTACGTGGACCAGGAA CT GGACATCAACCGGCTGTCCGACTACGATGTGGACCATATCGTGCCTCAGAGCTTTCTGAA GG ACGACTCCATCGACAACAAGGTGCTGACCAGAAGCGACAAGAACCGGGGCAAGAGCGACA AC GTGCCCTCCGAAGAGGTCGTGAAGAAGATGAAGAACTACTGGCGGCAGCTGCTGAACGCC AA GCTGATTACCCAGAGAAAGTTCGACAATCTGACCAAGGCCGAGAGAGGCGGCCTGAGCGA AC TGGATAAGGCCGGCTTCATCAAGAGACAGCTGGTGGAAACCCGGCAGATCACAAAGCACG TG GCACAGATCCTGGACTCCCGGATGAACACTAAGTACGACGAGAATGACAAGCTGATCCGG GA AGTGAAAGTGATCACCCTGAAGTCCAAGCTGGTGTCCGATTTCCGGAAGGATTTCCAGTT TT ACAAAGTGCGCGAGATCAACAACTACCACCACGCCCACGACGCCTACCTGAACGCCGTCG TG GGAACCGCCCTGATCAAAAAGTACCCTAAGCTGGAAAGCGAGTTCGTGTACGGCGACTAC AA GGTGTACGACGTGCGGAAGATGATCGCCAAGAGCGAGCAGGAAATCGGCAAGGCTACCGC CA AGTACTTCTTCTACAGCAACATCATGAACTTTTTCAAGACCGAGATTACCCTGGCCAACG GC GAGATCCGGAAGCGGCCTCTGATCGAGACAAACGGCGAAACCGGGGAGATCGTGTGGGAT AA GGGCCGGGATTTTGCCACCGTGCGGAAAGTGCTGAGCATGCCCCAAGTGAATATCGTGAA AA AGACCGAGGTGCAGACAGGCGGCTTCAGCAAAGAGTCTATCCTGCCCAAGAGGAACAGCG AT AAGCTGATCGCCAGAAAGAAGGACTGGGACCCTAAGAAGTACGGCGGCTTCGACAGCCCC AC CGTGGCCTATTCTGTGCTGGTGGTGGCCAAAGTGGAAAAGGGCAAGTCCAAGAAACTGAA GA GTGTGAAAGAGCTGCTGGGGATCACCATCATGGAAAGAAGCAGCTTCGAGAAGAATCCCA TC GACTTTCTGGAAGCCAAGGGCTACAAAGAAGTGAAAAAGGACCTGATCATCAAGCTGCCT AA GTACTCCCTGTTCGAGCTGGAAAACGGCCGGAAGAGAATGCTGGCCTCTGCCGGCGAACT GC AGAAGGGAAACGAACTGGCCCTGCCCTCCAAATATGTGAACTTCCTGTACCTGGCCAGCC AC TATGAGAAGCTGAAGGGCTCCCCCGAGGATAATGAGCAGAAACAGCTGTTTGTGGAACAG CA CAAGCACTACCTGGACGAGATCATCGAGCAGATCAGCGAGTTCTCCAAGAGAGTGATCCT GG CCGACGCTAATCTGGACAAAGTGCTGTCCGCCTACAACAAGCACCGGGATAAGCCCATCA GA GAGCAGGCCGAGAATATCATCCACCTGTTTACCCTGACCAATCTGGGAGCCCCTGCCGCC TT CAAGTACTTTGACACCACCATCGACCGGAAGAGGTACACCAGCACCAAAGAGGTGCTGGA CG CCACCCTGATCCACCAGAGCATCACCGGCCTGTACGAGACACGGATCGACCTGTCTCAGC TG GGAGGCGAC (SEQ ID NO: 16). [00156] In some embodiments, the construct comprising a promoter and a nuclease further comprises at least two inverted terminal repeat (ITR) sequences. In some embodiments, the construct comprising a promoter and a nuclease further comprises at least two ITR sequences from isolated or derived from an AAV of serotype 2 (AAV2). In some embodiments, the construct comprising a promoter and a nuclease further comprises at least two ITR sequences each comprising or consisting of a nucleotide sequence of GGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCG AC GCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGA (SEQ ID NO: 17). In some embodiments, the construct comprising a promoter and a nuclease further comprises at least two ITR sequences, wherein the first ITR sequence comprises or consists of a nucleotide sequence of CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTC GG GCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAAC TC CATCACTAGGGGTTCCT (SEQ ID NO: 18) and the second ITR sequence comprises or consist of a nucleotide sequence of AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGG CC GGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGA GC GCGCAGCTGCCTGCAGG (SEQ ID NO: 19). In some embodiments, the construct comprises or consists of, from 5’ to 3’ a first ITR, a sequence encoding a promoter, a sequence encoding a nuclease and a second ITR. In some embodiments, the construct comprises or consists of, from 5’ to 3’ a first AAV2 ITR, a sequence encoding an cTnT promoter, a sequence encoding a SpCas9 nuclease and a second AAV2 ITR. In some embodiments, the construct comprising or consisting of, from 5’ to 3’ a first ITR, a sequence encoding a promoter, a sequence encoding a nuclease and a second ITR, further comprises a poly A sequence. In some embodiments, the polyA sequence comprises or consists of a minipolyA sequence. Exemplary minipolyA sequences of the disclosure comprise or consist of a nucleotide sequence of TAGCAATAAAGGATCGTTTATTTTCATTGGAAGCGTGTGTTGGTTTTTTGATCAGGCGCG (SEQ ID NO: 20). In some embodiments, the construct comprises or consists of, from 5’ to 3’ a first ITR, a sequence encoding a promoter, a sequence encoding a nuclease, a poly A sequence and a second ITR. In some embodiments, the construct comprises or consists of, from 5’ to 3’ a first ITR, a sequence encoding a promoter, a sequence encoding a nuclease, a minipoly A sequence and a second ITR. In some embodiments, the construct comprises or consists of, from 5’ to 3’ a first AAV2 ITR, a sequence encoding an cTnT promoter, a sequence encoding a SpCas9 nuclease, a minipoly A sequence and a second AAV2 ITR. In some embodiments, the construct comprising, from 5’ to 3’ a first ITR, a sequence encoding a promoter, a sequence encoding a nuclease, a poly A sequence and a second ITR, further comprises at least one nuclear localization signal. In some embodiments, the construct comprising, from 5’ to 3’ a first ITR, a sequence encoding a promoter, a sequence encoding a nuclease, a poly A sequence and a second ITR, further comprises at least two nuclear localization signals. Exemplary nuclear localization signals of the disclosure comprise or consist of a nucleotide sequence of AAGCGTCCTGCTGCTACTAAGAAAGCTGGTCAAGCTAAGAAAAAGAAA (SEQ ID NO: 21) or a nucleotide sequence of ATGGCCCCAAAGAAGAAGCGGAAGGTCGGTATCCACGGAGTCCCAGCAGCC (SEQ ID NO: 22). In some embodiments, the construct comprises or consists of, from 5’ to 3’ a first ITR, a sequence encoding a promoter, a sequence encoding a first nuclear localization signal, a sequence encoding a nuclease, a poly A sequence and a second ITR. In some embodiments, the construct comprises or consists of, from 5’ to 3’ a first ITR, a sequence encoding a promoter, a sequence encoding a first nuclear localization signal, a sequence encoding a nuclease, a sequence encoding a second nuclear localization signal, a poly A sequence and a second ITR. In some embodiments, the construct comprising, from 5’ to 3’ a first ITR, a sequence encoding a promoter, a sequence encoding a first nuclear localization signal, a sequence encoding a nuclease, a sequence encoding a second nuclear localization signal, a poly A sequence and a second ITR, further comprises a stop codon. The stop codon may have a sequence of TAG, TAA, or TGA. In some embodiments, the construct comprises or consists of, from 5’ to 3’ a first ITR, a sequence encoding a promoter, a sequence encoding a first nuclear localization signal, a sequence encoding a nuclease, a sequence encoding a second nuclear localization signal, a stop codon, a poly A sequence and a second ITR. In some embodiments, the construct comprising or consisting of, from 5’ to 3’ a first ITR, a sequence encoding a promoter, a sequence encoding a first nuclear localization signal, a sequence encoding a nuclease, a sequence encoding a second nuclear localization signal, a stop codon, a poly A sequence and a second ITR, further comprises transposable element inverted repeats. Exemplary transposable element inverted repeats of the disclosure comprise or consist of a nucleotide sequence of TGTGGGCGGACAAAATAGTTGGGAACTGGGAGGGGTGGAAATGGAGTTTTTAAGGATTAT TT AGGGAAGAGTGACAAAATAGATGGGAACTGGGTGTAGCGTCGTAAGCTAATACGAAAATT AA AAATGACAAAATAGTTTGGAACTAGATTTCACTTATCTGGTT (SEQ ID NO: 23) and/or a nucleotide sequence of GAATATAGTCTTTACCATGCCCTTGGCCACGCCCCTCTTTAATACGACGGGCAATTTGCA CT TCAGAAAATGAAGAGTTTGCTTTAGCCATAACAAAAGTCCAGTATGCTTTTTCACAGCAT AA CTGGACTGATTTCAGTTTACAACTATTCTGTCTAGTTTAAGACTTTATTGTCATAGTTTA GA TCTATTTTGTTCAGTTTAAGACTTTATTGTCCGCCCACA (SEQ ID NO: 24). In some embodiments, the construct comprises or consists of, from 5’ to 3’ a first transposable element inverted repeat, a first ITR, a sequence encoding a promoter, a sequence encoding a first nuclear localization signal, a sequence encoding a nuclease, a sequence encoding a second nuclear localization signal, a stop codon, a poly A sequence, a second ITR, and a second transposable element inverted repeat. In some embodiments, the construct comprising or consisting of, from 5’ to 3’, a first transposable element inverted repeat, a first ITR, a sequence encoding a promoter, a sequence encoding a first nuclear localization signal, a sequence encoding a nuclease, a sequence encoding a second nuclear localization signal, a stop codon, a poly A sequence, a second ITR, and a second transposable element inverted repeat, further comprises a regulatory sequence. Exemplary regulatory sequences of the disclosure comprise or consist of a nucleotide sequence of CATGCAAGCTGTAGCCAACCACTAGAACTATAGCTAGAGTCCTGGGCGAACAAACGATGC TC GCCTTCCAGAAAACCGAGGATGCGAACCACTTCATCCGGGGTCAGCACCACCGGCAAGCG CC GCGACGGCCGAGGTCTTCCGATCTCCTGAAGCCAGGGCAGATCCGTGCACAGCACCTTGC CG TAGAAGAACAGCAAGGCCGCCAATGCCTGACGATGCGTGGAGACCGAAACCTTGCGCTCG TT CGCCAGCCAGGACAGAAATGCCTCGACTTCGCTGCTGCCCAAGGTTGCCGGGTGACGCAC AC CGTGGAAACGGATGAAGGCACGAACCCAGTTGACATAAGCCTGTTCGGTTCGTAAACTGT AA TGCAAGTAGCGTATGCGCTCACGCAACTGGTCCAGAACCTTGACCGAACGCAGCGGTGGT AA CGGCGCAGTGGCGGTTTTCATGGCTTGTTATGACTGTTTTTTTGTACAGTCTATGCCTCG GG CATCCAAGCAGCAAGCGCGTTACGCCGTGGGTCGATGTTTGATGTTATGGAGCAGCAACG AT GTTACGCAGCAGCAACGATGTTACGCAGCAGGGCAGTCGCCCTAAAACAAAGTTAGGTGG CT CAAGTATGGGCATCATTCGCACATGTAGGCTCGGCCCTGACCAAGTCAAATCCATGCGGG CT GCTCTTGATCTTTTCGGTCGTGAGTTCGGAGACGTAGCCACCTACTCCCAACATCAGCCG GA CTCCGATTACCTCGGGAACTTGCTCCGTAGTAAGACATTCATCGCGCTTGCTGCCTTCGA CC AAGAAGCGGTTGTTGGCGCTCTCGCGGCTTACGTTCTGCCCAAGTTTGAGCAGCCGCGTA GT GAGATCTATATCTATGATCTCGCAGTCTCCGGCGAGCACCGGAGGCAGGGCATTGCCACC GC GCTCATCAATCTCCTCAAGCATGAGGCCAACGCGCTTGGTGCTTATGTGATCTACGTGCA AG CAGATTACGGTGACGATCCCGCAGTGGCTCTCTATACAAAGTTGGGCATACGGGAAGAAG TG ATGCACTTTGATATCGACCCAAGTACCGCCACCTAACAATTCGTTCAAGCCGAGATCGGC TT CCCGGCCGCGGAGTTGTTCGGTAAATTGTCACAACGCCG (SEQ ID NO: 25). In some embodiments, the construct comprises or consists of, from 5’ to 3’ a first transposable element inverted repeat, a first ITR, a sequence encoding a promoter, a sequence encoding a first nuclear localization signal, a sequence encoding a nuclease, a sequence encoding a second nuclear localization signal, a stop codon, a poly A sequence, a second ITR, a regulatory sequence and a second transposable element inverted repeat. In some embodiments, the construct may further comprise one or more spacer sequences. Exemplary spacer sequences of the disclosure have length from 1-1500 nucleotides, inclusive of all ranges therebetween. In some embodiments, the spacer sequences may be located either 5’ to or 3’ to an ITR, a promoter, a nuclear localization sequence, a nuclease, a stop codon, a polyA sequence, a transposable element inverted repeat, and/or a regulator element. F. AAV-sgRNA vectors [00157] In some embodiments, at least a first sequence encoding a sgRNA and a second sequence encoding a sgRNA may be packaged into an AAV vector. In some embodiments, at least a first sequence encoding a sgRNA, a second sequence encoding a sgRNA, and a third sequence encoding a sgRNA may be packaged into an AAV vector. In some embodiments, at least a first sequence encoding a sgRNA, a second sequence encoding a sgRNA, a third sequence encoding a sgRNA, and a fourth sequence encoding a sgRNA may be packaged into an AAV vector. In some embodiments, at least a first sequence encoding a sgRNA, a second sequence encoding a sgRNA, a third sequence encoding a sgRNA, a fourth sequence encoding a sgRNA, and a fifth sequence encoding a sgRNA may be packaged into an AAV vector. In some embodiments, a plurality of sequences encoding a sgRNA are packaged into an AAV vector. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 sequences encoding a sgRNA may be packaged into an AAV vector. In some embodiments, each sequence encoding a sgRNA is different. In some embodiments, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 of the sequences encoding a sgRNA are the same. In some embodiments, all of the sequence encoding a sgRNA are the same. [00158] In some embodiments, the AAV vector is a wild-type AAV vector. In some embodiments, the AAV vector contains one or more mutations. In some embodiments, the AAV vector is isolated or derived from an AAV vector of serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 or any combination thereof. [00159] Exemplary AAV-sgRNA vectors contain two ITR (inverted terminal repeat) sequences which flank a central sequence region comprising the sgRNA sequences. In some embodiments, the ITRs are isolated or derived from an AAV vector of serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 or any combination thereof. In some embodiments, the ITRs are isolated or derived from an AAV vector of a first serotype and a sequence encoding a capsid protein of the AAV-sgRNA vector is isolated or derived from an AAV vector of a second serotype. In some embodiments, the first serotype and the second serotype are the same. In some embodiments, the first serotype and the second serotype are not the same. In some embodiments, the first serotype is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, or AAV11. In some embodiments, the second serotype is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, or AAV11. In some embodiments, the first serotype is AAV2 and the second serotype is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, or AAV11. In some embodiments, the first serotype is AAV2 and the second serotype is AAV9. [00160] Exemplary AAV-sgRNA vectors contain two ITR (inverted terminal repeat) sequences which flank a central sequence region comprising the sgRNA sequences. In some embodiments, the ITRs are isolated or derived from an AAV vector of serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 or any combination thereof. In some embodiments, a first ITR is isolated or derived from an AAV vector of a first serotype, a second ITR is isolated or derived from an AAV vector of a second serotype and a sequence encoding a capsid protein of the AAV-sgRNA vector is isolated or derived from an AAV vector of a third serotype. In some embodiments, the first serotype and the second serotype are the same. In some embodiments, the first serotype and the second serotype are not the same. In some embodiments, the first serotype, the second serotype, and the third serotype are the same. In some embodiments, the first serotype, the second serotype, and the third serotype are not the same. In some embodiments, the first serotype is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, or AAV11. In some embodiments, the second serotype is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, or AAV11. In some embodiments, the third serotype is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, or AAV11. In some embodiments, the first serotype is AAV2, the second serotype is AAV4 and the third serotype is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, or AAV11. In some embodiments, the first serotype is AAV2, the second serotype is AAV4 and the third serotype is AAV9. Exemplary AAV-sgRNA vectors contain two ITR (inverted terminal repeat) sequences which flank a central sequence region comprising the sgRNA sequences. In some embodiments, the ITRs are isolated or derived from an AAV vector of serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 or any combination thereof. In some embodiments, the ITRs comprise or consist of full-length and/or wild-type sequences for an AAV serotype. In some embodiments, the ITRs comprise or consist of truncated sequences for an AAV serotype. In some embodiments, the ITRs comprise or consist of elongated sequences for an AAV serotype. In some embodiments, the ITRs comprise or consist of sequences comprising a sequence variation compared to a wild-type sequence for the same AAV serotype. In some embodiments, the sequence variation comprises one or more of a substitution, deletion, insertion, inversion, or transposition. In some embodiments, the ITRs comprise or consist of at least 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150 base pairs. In some embodiments, the ITRs comprise or consist of 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150 base pairs. In some embodiments, the ITRs have a length of 110 ± 10 base pairs. In some embodiments, the ITRs have a length of 120 ± 10 base pairs. In some embodiments, the ITRs have a length of 130 ± 10 base pairs. In some embodiments, the ITRs have a length of 140 ± 10 base pairs. In some embodiments, the ITRs have a length of 150 ± 10 base pairs. In some embodiments, the ITRs have a length of 115, 145, or 141 base pairs. [00161] In some embodiments, the AAV-sgRNA vector may comprise additional elements to facilitate packaging of the vector and expression of the sgRNA. In some embodiments, the AAV-sgRNA vector may comprise a transposable element. In some embodiments, the AAV-sgRNA vector may comprise a regulatory element. In some embodiments, the regulatory element comprises an activator or a repressor. In some embodiments, the AAV-sgRNA sequence may comprise a non-functional or “stuffer” sequence. Exemplary stuffer sequences of the disclosure may have some (a non-zero percentage of) identity or homology to a genomic sequence of a mammal (including a human). Alternatively, exemplary stuffer sequences of the disclosure may have no identify or homology to a genomic sequence of a mammal (including a human). Exemplary stuffer sequences of the disclosure may comprise or consist of naturally occurring non-coding sequences or sequences that are neither transcribed nor translated following administration of the AAV vector to a subject. [00162] In some embodiments, the AAV-sgRNA vector may be optimized for production in yeast, bacteria, insect cells, or mammalian cells. In some embodiments, the AAV-sgRNA vector may be optimized for expression in human cells. In some embodiments, the AAV-Cas9 vector may be optimized for expression in a bacculovirus expression system. [00163] In some embodiments, the AAV-sgRNA vector comprises at least one promoter. In some embodiments, the AAV-sgRNA vector comprises at least two promoters. In some embodiments, the AAV-sgRNA vector comprises at least three promoters. In some embodiments, the AAV-sgRNA vector comprises at least four promoters. In some embodiments, the AAV-sgRNA vector comprises at least five promoters. Exemplary promoters include, for example, immunoglobulin light chain, immunoglobulin heavy chain, T-cell receptor, HLA DQ a and/or DQ β, β-interferon, interleukin-2, interleukin-2 receptor, MHC class II 5, MHC class II HLA-Dra, β-Actin, muscle creatine kinase (MCK), prealbumin (transthyretin), elastase I, metallothionein (MTII), collagenase, albumin, α-fetoprotein, t- globin, β-globin, c-fos, c-HA-ras, insulin, neural cell adhesion molecule (NCAM), α ₁ - antitrypain, H2B (TH2B) histone, mouse and/or type I collagen, glucose-regulated proteins (GRP94 and GRP78), rat growth hormone, human serum amyloid A (SAA), troponin I (TN I), platelet-derived growth factor (PDGF), duchenne muscular dystrophy, SV40, polyoma, retroviruses, papilloma virus, hepatitis B virus, human immunodeficiency virus, cytomegalovirus (CMV), and gibbon ape leukemia virus. Further exemplary promoters include the U6 promoter, the H1 promoter, and the 7SK promoter. [00164] In some embodiments, the AAV vector comprises a first sequence encoding a sgRNA and a second sequence encoding a sgRNA, a first promoter drives expression of the first sequence encoding a sgRNA and a second promoter drives expression of the second sequence encoding a sgRNA. In some embodiments, the first and second promoters are the same. In some embodiments, the first and second promoters are different. In some embodiments, the first and second promoters are selected from the H1 promoter, the U6 promoter, and the 7SK promoter. In some embodiments, the first sequence encoding a sgRNA and the second sequence encoding a sgRNA are identical. In some embodiments, the first sequence encoding a sgRNA and the second sequence encoding a sgRNA are not identical. [00165] In some embodiments, the AAV vector comprises a first sequence encoding a sgRNA, a second sequence encoding a sgRNA, and a third sequence encoding a sgRNA, a first promoter drives expression of the first sequence encoding a sgRNA, a second promoter drives expression of the second sequence encoding a sgRNA, and a third promoter drives expression of a third sequence encoding a sgRNA. In some embodiments, at least two of the first, second, and third promoters are the same. In some embodiments, each of the first, second, and third promoters are different. In some embodiments, the first, second, and third promoters are selected from the H1 promoter, the U6 promoter, and the 7SK promoter. In some embodiments, the first promoter is the U6 promoter. In some embodiments, the second promoter is the H1 promoter. In some embodiments, the third promoter is the 7SK promoter. In some embodiments, the first promoter is the U6 promoter, the second promoter is the H1 promoter, and the third promoter is the 7SK promoter. In some embodiments, the first sequence encoding a sgRNA, the second sequence encoding a sgRNA, and the third sequence encoding a sgRNA are identical. In some embodiments, the first sequence encoding a sgRNA, the second sequence encoding a sgRNA, and the third sequence encoding a sgRNA are not identical. [00166] In some embodiments, the AAV vector comprises a first sequence encoding a sgRNA, a second sequence encoding a sgRNA, a third sequence encoding a sgRNA, and a fourth sequence encoding a sgRNA, a first promoter drives expression of the first sequence encoding a sgRNA, a second promoter drives expression of the second sequence encoding a sgRNA, a third promoter drives expression of the third sequence encoding a sgRNA, and a fourth promoter drives expression of the fourth sequence encoding a sgRNA. In some embodiments, at least two of the first, second, third, and fourth promoters are the same. In some embodiments, each of the first, second, third, and fourth promoters are different. In some embodiments, each of the first, second, third and fourth promoters are selected from the H1 promoter, the U6 promoter, and the 7SK promoter. In some embodiments, the first sequence encoding a sgRNA, the second sequence encoding a sgRNA, the third sequence encoding a sgRNA, and the fourth sequence encoding a sgRNA are identical. In some embodiments, the first sequence encoding a sgRNA, the second sequence encoding a sgRNA, the third sequence encoding a sgRNA, and the fourth sequence encoding a sgRNA are not identical. [00167] In some embodiments, the AAV vector comprises a first sequence encoding a sgRNA, a second sequence encoding a sgRNA, a third sequence encoding a sgRNA, a fourth sequence encoding a sgRNA, and a fifth sequence encoding a sgRNA, a first promoter drives expression of the first sequence encoding a sgRNA, a second promoter drives expression of the second sequence encoding a sgRNA, a third promoter drives expression of the third sequence encoding a sgRNA, a fourth promoter drives expression of the fourth sequence encoding a sgRNA, and a fifth promoter drives expression of the fifth sequence encoding a sgRNA. In some embodiments, at least two of the first, second, third, fourth, and fifth promoters are the same. In some embodiments, each of the first, second, third, fourth, and fifth promoters are different. In some embodiments, each of the first, second, third, and fourth promoters are different. In some embodiments, each of the first, second, third, fourth and fifth promoters are selected from the H1 promoter, the U6 promoter, and the 7SK promoter. In some embodiments, the first sequence encoding a sgRNA, the second sequence encoding a sgRNA, the third sequence encoding a sgRNA, the fourth sequence encoding a sgRNA, and the fifth sequence encoding a sgRNA are identical. In some embodiments, the first sequence encoding a sgRNA, the second sequence encoding a sgRNA, the third sequence encoding a sgRNA, the fourth sequence encoding a sgRNA, and the fifth sequence encoding a sgRNA are not identical. V. Pharmaceutical Compositions and Delivery Methods [00168] For clinical applications, pharmaceutical compositions are prepared in a form appropriate for the intended application. Generally, this entails preparing compositions that are essentially free of pyrogens, as well as other impurities that could be harmful to humans or animals. [00169] Appropriate salts and buffers are used to render drugs, proteins or delivery vectors stable and allow for uptake by target cells. Aqueous compositions of the present disclosure comprise an effective amount of the drug, vector or proteins, dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. The phrase “pharmaceutically or pharmacologically acceptable” refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human. As used herein, “pharmaceutically acceptable carrier” includes solvents, buffers, solutions, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like acceptable for use in formulating pharmaceuticals, such as pharmaceuticals suitable for administration to humans. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent that is not incompatible with the active ingredients of the present disclosure, its use in therapeutic compositions may be used. Supplementary active ingredients also can be incorporated into the compositions, provided they do not inactivate the vectors or cells of the compositions. [00170] In some embodiments, the active compositions of the present disclosure may include classic pharmaceutical preparations. Administration of these compositions according to the present disclosure may be via any common route so long as the target tissue is available via that route, but generally including systemic administration. This includes oral, nasal, or buccal. Alternatively, administration may be by intradermal, subcutaneous, intramuscular, intracardiac, intraperitoneal or intravenous injection, or by direct injection into muscle tissue. Such compositions would normally be administered as pharmaceutically acceptable compositions, as described supra. [00171] The active compounds may also be administered parenterally or intraperitoneally. By way of illustration, solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations generally contain a preservative to prevent the growth of microorganisms. [00172] The pharmaceutical forms suitable for injectable use include, for example, sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Generally, these preparations are sterile and fluid to the extent that easy injectability exists. Preparations should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Appropriate solvents or dispersion media may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. [00173] Sterile injectable solutions may be prepared by incorporating the active compounds in an appropriate amount into a solvent along with any other ingredients (for example as enumerated above) as desired, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the desired other ingredients, e.g., as enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation include vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient(s) plus any additional desired ingredient from a previously sterile-filtered solution thereof. [00174] In some embodiments, the compositions of the present disclosure are formulated in a neutral or salt form. Pharmaceutically acceptable salts include, for example, acid addition salts (formed with the free amino groups of the protein) derived from inorganic acids (e.g., hydrochloric or phosphoric acids, or from organic acids (e.g., acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups of the protein can also be derived from inorganic bases (e.g., sodium, potassium, ammonium, calcium, or ferric hydroxides) or from organic bases (e.g., isopropylamine, trimethylamine, histidine, procaine) and the like. [00175] Upon formulation, solutions are preferably administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations may easily be administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like. For parenteral administration in an aqueous solution, for example, the solution generally is suitably buffered and the liquid diluent first rendered isotonic for example with sufficient saline or glucose. Such aqueous solutions may be used, for example, for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Preferably, sterile aqueous media are employed as is known to those of skill in the art, particularly in light of the present disclosure. By way of illustration, a single dose may be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences" 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards. [00176] In some embodiments, the nucleotide editing Cas9 and sgRNAs described herein may be delivered to the patient using adoptive cell transfer (ACT). In adoptive cell transfer, one or more expression constructs are provided ex vivo to cells which have originated from the patient (autologous) or from one or more individual(s) other than the patient (allogeneic). The cells are subsequently introduced or reintroduced into the patient. Thus, in some embodiments, one or more nucleic acids encoding nucleotide editing Cas9 and a guide ^{RNA that targets a CaMKIIδ splice site are provided to a cell ex vivo before the cell is} introduced or reintroduced to a patient. VI. Definitions [00177] The term “nucleotide editing Cas9” refers to a Cas9 protein fused to a base editor. Non-limiting examples of Cas9 include SpCas9, SpCas9-NG, SpRY, SaCas9, SaCas9-KKH, SauCas9, and SlugCas9. Non limiting examples of a base editor include ABEmax, ABE8e, ABE8eV106W, ABE8.20-m. [00178] The terms “polynucleotide,” “nucleic acid” and “transgene” are used interchangeably herein to refer to all forms of nucleic acid, oligonucleotides, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and polymers thereof. Polynucleotides include genomic DNA, cDNA and antisense DNA, and spliced or unspliced mRNA, rRNA, tRNA and inhibitory DNA or RNA (RNAi, e.g., small or short hairpin (sh)RNA, microRNA (miRNA), small or short interfering (si)RNA, trans-splicing RNA, or antisense RNA). Polynucleotides can include naturally occurring, synthetic, and intentionally modified or altered polynucleotides (e.g., variant nucleic acid). Polynucleotides can be single stranded, double stranded, or triplex, linear or circular, and can be of any suitable length. In discussing polynucleotides, a sequence or structure of a particular polynucleotide may be described herein according to the convention of providing the sequence in the 5ʹ to 3ʹ direction. A nucleic acid “backbone” can be made up of a variety of linkages, including one or more of sugar-phosphodiester linkages, peptide-nucleic acid bonds (“peptide nucleic acids” or PNA; PCT No. WO 95/32305), phosphorothioate linkages, methylphosphonate linkages, or combinations thereof. Sugar moieties of a nucleic acid can be ribose, deoxyribose, or similar compounds with substitutions, e.g., 2’ methoxy or 2’ halide substitutions. Nitrogenous bases can be conventional bases (A, G, C, T, U), analogs thereof (e.g., modified uridines such as 5- methoxyuridine, pseudouridine, or N1-methylpseudouridine, or others); inosine; derivatives of purines or pyrimidines (e.g., N ⁴ -methyl deoxyguanosine, deaza- or aza-purines, deaza- or aza- pyrimidines, pyrimidine bases with substituent groups at the 5 or 6 position (e.g., 5- methylcytosine), purine bases with a substituent at the 2, 6, or 8 positions, 2-amino-6- methylaminopurine, O ⁶ -methylguanine, 4-thio-pyrimidines, 4-amino-pyrimidines, 4- dimethylhydrazine-pyrimidines, and O ⁴ -alkyl-pyrimidines; U.S. Patent 5,378,825 and PCT No. WO 93/13121). For general discussion see The Biochemistry of the Nucleic Acids 5-36, Adams et al., ed., 11 ^th ed., 1992). Nucleic acids can include one or more “abasic” residues where the backbone includes no nitrogenous base for position(s) of the polymer (U.S. Patent 5,585,481). A nucleic acid can comprise only conventional RNA or DNA sugars, bases and linkages, or can include both conventional components and substitutions (e.g., conventional bases with 2’ methoxy linkages, or polymers containing both conventional bases and one or more base analogs). Nucleic acid includes “locked nucleic acid” (LNA), an analogue containing one or more LNA nucleotide monomers with a bicyclic furanose unit locked in an RNA mimicking sugar conformation, which enhance hybridization affinity toward complementary RNA and DNA sequences (Vester and Wengel, 2004, Biochemistry 43(42):13233-41). RNA and DNA have different sugar moieties and can differ by the presence of uracil or analogs thereof in RNA and thymine or analogs thereof in DNA. [00179] A nucleic acid encoding a polypeptide often comprises an open reading frame that encodes the polypeptide. Unless otherwise indicated, a particular nucleic acid sequence also includes degenerate codon substitutions. [00180] Nucleic acids can include one or more expression control or regulatory elements operably linked to the open reading frame, where the one or more regulatory elements are configured to direct the transcription and translation of the polypeptide encoded by the open reading frame in a mammalian cell. Non-limiting examples of expression control/regulatory elements include transcription initiation sequences (e.g., promoters, enhancers, a TATA box, and the like), translation initiation sequences, mRNA stability sequences, poly A sequences, secretory sequences, and the like. Expression control/regulatory elements can be obtained from the genome of any suitable organism. [00181] As used herein, “AAV” refers to an adeno-associated virus vector. As used herein, “AAV” refers to any AAV serotype and variant, including but not limited to an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh10 (see, e.g., SEQ ID NO: 81 of US 9,790,472, which is incorporated by reference herein in its entirety), AAVrh74 (see, e.g., SEQ ID NO: 1 of US 2015/0111955, which is incorporated by reference herein in its entirety), AAV9 vector, AAV9P vector (also known as AAVMYO, see, Weinmann et al., 2020, Nature Communications, 11:5432), and Myo-AAV vectors described in Tabebordbar et al., 2021, Cell, 184:1-20 (e.g., MyoAAV 1A, 2A, 3A, 4A, 4C, or 4E) , wherein the number following AAV indicates the AAV serotype. The term “AAV” can also refer to any known AAV (vector) system. In some embodiments, the AAV vector is a single-stranded AAV (ssAAV). In some embodiments, the AAV vector is a double-stranded AAV (dsAAV). Any variant of an AAV vector or serotype thereof, such as a self-complementary AAV (scAAV) vector, is encompassed within the general terms AAV vector, AAV1 vector, etc. See, e.g., McCarty et al., Gene Ther. 2001; 8:1248–54, Naso et al., BioDrugs 2017; 31:317-334, and references cited therein for detailed discussion of various AAV vectors. Structurally, AAVs are small (25 nm), single-DNA stranded non-enveloped viruses with an icosahedral capsid. Naturally occurring or engineered AAV serotypes and variants that differ in the composition and structure of their capsid protein have varying tropism, i.e., ability to transduce different cell types. When combined with active promoters, this tropism defines the site of gene expression. [00182] “Guide RNA”, “guide RNA”, and simply “guide” are used herein interchangeably to refer to either a crRNA (also known as CRISPR RNA), or the combination of a crRNA and a trRNA (also known as tracrRNA). The crRNA and trRNA may be associated as a single RNA molecule (single guide RNA, sgRNA) or in two separate RNA molecules (dual guide RNA, dgRNA). “Guide RNA” or “guide RNA” refers to each type. The trRNA may be a naturally occurring sequence, or a trRNA sequence with modifications or variations compared to naturally occurring sequences. For clarity, the terms “guide RNA” or “guide” as used herein, and unless specifically stated otherwise, may refer to an RNA molecule (comprising A, C, G, and U nucleotides) or to a DNA molecule encoding such an RNA molecule (comprising A, C, G, and T nucleotides) or complementary sequences thereof. In general, in the case of a DNA nucleic acid construct encoding a guide RNA, the U residues in any of the RNA sequences described herein may be replaced with T residues, and in the case of a guide RNA construct encoded by any of the DNA sequences described herein, the T residues may be replaced with U residues. [00183] Target sequences for Cas9s include both the positive and negative strands of genomic DNA (i.e., the sequence given and the sequence’s reverse complement), as a nucleic acid substrate for a Cas9 is a double stranded nucleic acid. Accordingly, where a guide sequence is said to be “complementary to a target sequence”, it is to be understood that the guide sequence may direct a guide RNA to bind to the reverse complement of a target sequence. Thus, in some embodiments, where the guide sequence binds the reverse complement of a target sequence, the guide sequence is identical to certain nucleotides of the target sequence (e.g., the target sequence not including the PAM) except for the substitution of U for T in the guide sequence. [00184] A “promoter” refers to a nucleotide sequence, usually upstream (5') of a coding sequence, which directs and/or controls the expression of the coding sequence by providing the recognition for RNA polymerase and other factors required for proper transcription. "Promoter" includes a minimal promoter that is a short DNA sequence comprised of a TATA-box and optionally other sequences that serve to specify the site of transcription initiation, to which regulatory elements are added for control of expression. [00185] An “enhancer” is a DNA sequence that can stimulate transcription activity and may be an innate element of the promoter or a heterologous element that enhances the level or tissue specificity of expression. It is capable of operating in either orientation (5’- >3’ or 3’->5’) and may be capable of functioning even when positioned either upstream or downstream of the promoter. [00186] Promoters and/or enhancers may be derived in their entirety from a native gene or be composed of different elements derived from different elements found in nature, or even be comprised of synthetic DNA segments. A promoter or enhancer may comprise DNA sequences that are involved in the binding of protein factors that modulate/control effectiveness of transcription initiation in response to stimuli, physiological or developmental conditions. [00187] Non-limiting examples include SV40 early promoter, mouse mammary tumor virus LTR promoter; adenovirus major late promoter (Ad MLP); a herpes simplex virus (HSV) promoter, a cytomegalovirus (CMV) promoter such as the CMV immediate early promoter region (CMVIE), a rous sarcoma virus (RSV) promoter, pol II promoters, pol III promoters, synthetic promoters, hybrid promoters, and the like. In addition, sequences derived from non-viral genes, such as the murine metallothionein gene, will also find use herein. Exemplary constitutive promoters include the promoters for the following genes which encode certain constitutive or “housekeeping” functions: hypoxanthine phosphoribosyl transferase (HPRT), dihydrofolate reductase (DHFR), adenosine deaminase, phosphoglycerol kinase (PGK), pyruvate kinase, phosphoglycerol mutase, the actin promoter, and other constitutive promoters known to those of skill in the art. In addition, many viral promoters function constitutively in eukaryotic cells. These include: the early and late promoters of SV40; the long terminal repeats (LTRs) of Moloney Leukemia Virus and other retroviruses; and the thymidine kinase promoter of Herpes Simplex Virus, among many others. Accordingly, any of the above- referenced constitutive promoters can be used to control transcription of a heterologous gene insert. [00188] A “transgene” is used herein to conveniently refer to a nucleic acid sequence/polynucleotide that is intended or has been introduced into a cell or organism. Transgenes include any nucleic acid, such as a gene that encodes an inhibitory RNA or polypeptide or protein, and are generally heterologous with respect to naturally occurring AAV genomic sequences. [00189] The term “transduce” refers to introduction of a nucleic acid sequence into a cell or host organism by way of a vector (e.g., a viral particle). Introduction of a transgene into a cell by a viral particle can therefore be referred to as “transduction” of the cell. The transgene may or may not be integrated into genomic nucleic acid of a transduced cell. If an introduced transgene becomes integrated into the nucleic acid (genomic DNA) of the recipient cell or organism it can be stably maintained in that cell or organism and further passed on to or inherited by progeny cells or organisms of the recipient cell or organism. Finally, the introduced transgene may exist in the recipient cell or host organism extrachromosomally, or only transiently. A “transduced cell” is therefore a cell into which the transgene has been introduced by way of transduction. Thus, a “transduced” cell is a cell into which, or a progeny thereof in which a transgene has been introduced. A transduced cell can be propagated, transgene transcribed and the encoded inhibitory RNA or protein expressed. For gene therapy uses and methods, a transduced cell can be in a mammal. [00190] A nucleic acid/transgene is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence. A nucleic acid/transgene encoding an RNAi or a polypeptide, or a nucleic acid directing expression of a polypeptide may include an inducible promoter, or a tissue-specific promoter for controlling transcription of the encoded polypeptide. A nucleic acid operably linked to an expression control element can also be referred to as an expression cassette. [00191] As used herein, the terms “modify” or “variant” and grammatical variations thereof, mean that a nucleic acid, polypeptide or subsequence thereof deviates from a reference sequence. Modified and variant sequences may therefore have substantially the same, greater or less expression, activity or function than a reference sequence, but at least retain partial activity or function of the reference sequence. A particular type of variant is a mutant protein, which refers to a protein encoded by a gene having a mutation, e.g., a missense or nonsense mutation. [00192] In general, “CRISPR system” refers collectively to transcripts and other elements involved in the expression of or directing the activity of CRISPR-associated (“Cas”) genes, including sequences encoding a Cas gene, a tracr (trans-activating CRISPR) sequence (e.g., tracrRNA or an active partial tracrRNA), a tracr-mate sequence (encompassing a “direct repeat” and a tracrRNA-processed partial direct repeat in the context of an endogenous CRISPR system), a guide sequence (also referred to as a “spacer” in the context of an endogenous CRISPR system), and/or other sequences and transcripts from a CRISPR locus. [00193] As used herein, a “spacer sequence,” sometimes also referred to herein and in the literature as a “spacer,” “protospacer,” “guide sequence,” or “targeting sequence” refers to a sequence within a guide RNA that is complementary to a target sequence and functions to direct a guide RNA to a target sequence for cleavage by a Cas9. For clarity, the terms “spacer sequence”, “spacer,” “protospacer,” “guide sequence,” or “targeting sequence” as used herein, and unless specifically stated otherwise, may refer to an RNA molecule (comprising A, C, G, and U nucleotides) or to a DNA molecule encoding such an RNA molecule (comprising A, C, G, and T nucleotides) or complementary sequences thereof. [00194] A “nucleic acid” or “polynucleotide” variant refers to a modified sequence which has been genetically altered compared to wild-type. The sequence may be genetically modified without altering the encoded protein sequence. Alternatively, the sequence may be genetically modified to encode a variant protein. A nucleic acid or polynucleotide variant can also refer to a combination sequence which has been codon modified to encode a protein that still retains at least partial sequence identity to a reference sequence, such as wild-type protein sequence, and also has been codon-modified to encode a variant protein. For example, some codons of such a nucleic acid variant will be changed without altering the amino acids of a protein encoded thereby, and some codons of the nucleic acid variant will be changed which in turn changes the amino acids of a protein encoded thereby. [00195] The terms “protein” and “polypeptide” are used interchangeably herein. The “polypeptides” encoded by a “nucleic acid” or “polynucleotide” or “transgene” disclosed herein include partial or full-length native sequences, as with naturally occurring wild-type and functional polymorphic proteins, functional subsequences (fragments) thereof, and sequence variants thereof, so long as the polypeptide retains some degree of function or activity. Accordingly, in methods and uses of the disclosure, such polypeptides encoded by nucleic acid sequences are not required to be identical to the endogenous protein that is defective, or whose activity, function, or expression is insufficient, deficient or absent in a treated mammal. [00196] An example of an amino acid modification is a conservative amino acid substitution or a deletion. In particular embodiments, a modified or variant sequence retains at least part of a function or activity of the unmodified sequence (e.g., wild-type sequence). [00197] Another example of an amino acid modification is a targeting peptide introduced into a capsid protein of a viral particle. Peptides have been identified that target recombinant viral vectors or nanoparticles to various organs and tissues. [00198] A “variant” of a molecule is a sequence that is substantially similar to the sequence of the native molecule. For nucleotide sequences, variants include those sequences that, because of the degeneracy of the genetic code, encode the identical amino acid sequence of the native protein. Naturally occurring allelic variants such as these can be identified with the use of molecular biology techniques, as, for example, with polymerase chain reaction (PCR) and hybridization techniques. Variant nucleotide sequences also include synthetically derived nucleotide sequences, such as those generated, for example, by using site- directed mutagenesis, which encode the native protein, as well as those that encode a polypeptide having amino acid substitutions. Generally, nucleotide sequence variants of the disclosure will have at least 40%, 50%, 60%, to 70%, e.g., 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, to 79%, generally at least 80%, e.g., 81%-84%, at least 85%, e.g., 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, to 98%, sequence identity to the native (endogenous) nucleotide sequence. In certain embodiments, the variant is biologically functional (i.e., retains 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% of activity or function of wild-type). [00199] “Conservative variations” of a particular nucleic acid sequence refers to those nucleic acid sequences that encode identical or essentially identical amino acid sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given polypeptide. For instance, the codons CGT, CGC, CGA, CGG, AGA and AGG all encode the amino acid arginine. Thus, at every position where an arginine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded protein. Such nucleic acid variations are “silent variations,” which are one species of “conservatively modified variations.” Every nucleic acid sequence described herein that encodes a polypeptide also describes every possible silent variation, except where otherwise noted. One of skill in the art will recognize that each codon in a nucleic acid (except ATG, which is ordinarily the only codon for methionine) can be modified to yield a functionally identical molecule by standard techniques. Accordingly, each “silent variation” of a nucleic acid that encodes a polypeptide is implicit in each described sequence. [00200] The term “substantial identity” of polynucleotide sequences means that a polynucleotide comprises a sequence that has at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, or 79%, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, or 89%, or at least 90%, 91%, 92%, 93%, or 94%, or even at least 95%, 96%, 97%, 98%, or 99% sequence identity, compared to a reference sequence using one of the alignment programs described using standard parameters. One of skill in the art will recognize that these values can be appropriately adjusted to determine corresponding identity of proteins encoded by two nucleotide sequences by taking into account codon degeneracy, amino acid similarity, reading frame positioning, and the like. Substantial identity of amino acid sequences for these purposes normally means sequence identity of at least 70%, at least 80%, 90%, or even at least 95%. [00201] The term “substantial identity” in the context of a polypeptide indicates that a polypeptide comprises a sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, or 79%, or 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, or 89%, or at least 90%, 91%, 92%, 93%, or 94%, or even, 95%, 96%, 97%, 98% or 99%, sequence identity to the reference sequence over a specified comparison window. An indication that two polypeptide sequences are identical is that one polypeptide is immunologically reactive with antibodies raised against the second polypeptide. Thus, a polypeptide is identical to a second polypeptide, for example, where the two peptides differ only by a conservative substitution. [00202] The terms “treat” and “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent, inhibit, reduce, or decrease an undesired physiological change or disorder, such as the development, progression or worsening of the disorder. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilizing a (i.e., not worsening or progressing) symptom or adverse effect of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those predisposed (e.g., as determined by a genetic assay). [00203] As used herein the specification, “a” or “an” may mean one or more. As used herein in the claim(s), when used in conjunction with the word “comprising,” the words “a” or “an” may mean one or more than one. [00204] The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” As used herein “another” may mean at least a second or more. [00205] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the inherent variation in the method being employed to determine the value, the variation that exists among the study subjects, or a value that is within 10% of a stated value. [00206] As used herein, “essentially free,” in terms of a specified component, is used herein to mean that none of the specified component has been purposefully formulated into a composition and/or is present only as a contaminant or in trace amounts. The total amount of the specified component resulting from any unintended contamination of a composition is therefore well below 0.05%, preferably below 0.01%. Most preferred is a composition in which no amount of the specified component can be detected with standard analytical methods. VII. Examples [00207] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. Example 1 – Materials and Methods [00208] Study design and approval. The aim of the present study was to develop a therapeutic approach for cardiac disease by using CRISPR-Cas9 nucleotide base editing. The inventors designed a gene editing system to ablate the oxidative activation sites of CaMKIIδ, which cause pathological enzyme activation. Different editing approaches were first screened in HEK293 cells. The two most efficient sgRNAs were then tested for their biologic effect in human cardiomyocytes derived from induced pluripotent stem cells (iPSCs). The inventors then applied the CRISPR-Cas9 base editing system with the best therapeutic in vitro effect to adult mice that were subjected to ischemia/reperfusion (IR) injury. [00209] All experiments were performed in replicates. For all in vivo experiments, the inventors used eight C57Bl6 mice at 12 weeks of age per group. Mice were randomly assigned to sham surgery or to IR with either no injection, intracardiac injection of a control virus or intracardiac injection of a CaMKIIδ editing system. Echocardiography was performed on each mouse before IR as well as 24 hours, one week, two weeks, and three weeks after IR. Cardiac magnetic resonance imaging was performed in five mice per group at four weeks post-IR. After five weeks, all mice were euthanized, and five out of eight mice per group were dedicated to molecular analyses and three mice to histological analyses. The inventors did not use a statistical test to predetermine the sample size. All samples are included in the study, with no data excluded. Each experimental procedure involving animals has been reviewed and approved by the University of Texas Southwestern Medical Center’s Institutional Animal Care and Use Committee. [00210] Plasmids and cloning. Plasmids were ordered from Addgene. The sgRNAs (listed in Table S1) were cloned into a pmCherry_sgRNA plasmid containing a U6- driven sgRNA scaffold and a cytomegalovirus (CMV)–driven pmCherry fluorescent protein (gift from Ervin Welker, Addgene plasmid #80457, n2t.net/addgene:80457; RRID: Addgene_80457). [00211] pCMV_ABEmax_P2A_GFP (Addgene plasmid #112101, n2t.net/addgene:112101, RRID: Addgene_112101) (Koblan et al., 2018), NG-ABEmax (Addgene plasmid #124163, n2t.net/addgene:124163, RRID: Addgene_124163) (Huang et al., 2019), ABE8e (Addgene plasmid #138489, n2t.net/addgene:138489, RRID: Addgene_138489) (Richter et al., 2020), and NG-ABE8e (Addgene #138491, n2t.net/addgene:138491, RRID: Addgene_138491) (Richter et al., 2020) were gifts from David Liu. pCMV-T7-ABEmax(7.10)-SpRY-P2A-EGFP (RTW5025) was a gift from Benjamin Kleinstiver (Addgene plasmid #140003, n2t.net/addgene:140003, RRID: Addgene_140003) (Walton et al., 2020). ABE8e-SpRY was obtained by adapting pCMV-T7-ABEmax(7.10)- SpRY-P2A-EGFP (RTW5025). [00212] For the in vivo experiments, the N- and C-terminal ABE constructs were adapted from Cbh_v5 AAV-ABE N-terminal (gift from David Liu, Addgene plasmid #137177, n2t.net/addgene:137177, RRID: Addgene_137177) (Levy et al., 2020) and Cbh_v5 AAV-ABE C-terminal (gift from David Liu, Addgene plasmid #137178, n2t.net/addgene:137178, RRID: Addgene_137178) (Levy et al., 2020), respectively, to carry ABE8e-SpRY (driven by a cardiac troponin T promoter) and mouse sgRNA6 (driven by a U6 promoter). A split-intein trans- splicing system enabled reassembly to a functional ABE system in vivo, as previously described (Chemello et al., 2021). [00213] Adaptions were performed using oligonucleotides (IDT) or products of PCR amplification of appropriate template sequences with PrimeStar GXL Polymerase (Takara). Oligonucleotides and PCR products were cloned into restriction enzyme-digested vectors using NEBuilder HiFi DNA Assembly (NEB). [00214] TOPO-TA (topoisomerase-based thymine adenine) cloning of cDNA PCR products (TOPO™ TA Cloning™ Kit, Invitrogen) with subsequent sequencing was used to further confirm successful gene editing in vivo. [00215] Cell culture and transfection. HEK293 (ATCC) and N2a (ATCC) cells were cultured in Dulbecco’s modified Eagle’s medium (Sigma-Aldrich) containing 10% (v/v) fetal bovine serum (GeminiBio). For transfection, cells were plated onto 24-well plates (Corning) with approximately 125,000 cells per well. After 24 h, cells were transfected with plasmids expressing the base editing components using Lipofectamine 2000 (Thermo Fisher Scientific) according to the manufacturer’s instructions. Three days after the transfection, cells were harvested to assess the editing efficiency. [00216] Human iPSC culture and nucleofection. Human iPSCs (previously generated and used in the inventors’ laboratory (Chemello et al., 2021)) were maintained on Matrigel (Corning)-coated 6-well polystyrene culture plates in mTeSR ^TM 1 media (STEMCELL). At 70-80% confluency, they were passaged using Versene (Thermo Fisher Scientific). [00217] Approximately 8x10 ⁵ iPSCs were used for nucleofection experiments and they were subjected to 10 μM ROCK inhibitor (Y-27632, Selleckchem) one hour earlier. Single cell status was obtained using Accutase (Innovative Cell Technologies). The iPSCs were mixed either with 1.5 μg of pmCherry_sgRNA plasmid carrying sgRNA1 and 4.5 μg ABE8e plasmid or with 1.5 μg of pmCherry_sgRNA plasmid carrying sgRNA6 and 4.5 μg ABE8e- SpRY plasmid. P3 Primary Cell 4D-Nucleofector X Kit (Lonza) was used according to the manufacturer’s protocol to nucleofect iPSCs. ROCK inhibitor (10 μM) and Primocin (100 μg/mL) (InvivoGen) were then added to the culture media and incubated for one day. Two days after the nucleofection, pmCherry and green fluorescent protein (GFP) double-positive cells were collected by fluorescence-activated cell sorting and clonally expanded to establish the M281V (sgRNA1) and MMH281/282/283VVR (sgRNA6) iPSC lines. [00218] Sanger sequencing analysis. DirectPCR cell lysis reagent (Viagen) with proteinase K (1 μg/μL) was used according to the manufacturer’s recommendations to isolate genomic DNA of human HEK293 cells, human iPSCs, and mouse N2a cells. DNA was amplified using PrimeSTAR GXL DNA polymerase (Takara) with the primers listed in Table S2 and the PCR product was cleaned using ExoSap-IT Express (Thermo Fisher Scientific). The editing efficiency was determined by analyzing the Sanger chromatograms with EditR (Kluesner et al., 2018). [00219] Deep amplicon sequencing analysis. Deep amplicon sequencing was used to measure the on-target editing efficiency for CaMKIIδ in human iPSCs and in cardiac tissue from mice treated with AAV-ABE-sgRNA6. DNeasy Blood & Tissue Kit (Qiagen) was used to isolate genomic DNA. TRIzol (Thermo Fisher Scientific) and RNeasy Mini Kit (Qiagen) were used to isolate total RNA from whole hearts that was reverse transcribed using iScript Reverse Transcription Supermix (Bio-Rad) with random primers. On-target sites for human CaMKIIδ DNA, mouse CaMKIIδ DNA, and mouse CaMKIIδ cDNA were PCR amplified using PrimeStar GXL Polymerase (Takara) with the primers listed in Table S3. In a second PCR round, Illumina flow cell binding sequences and barcodes were added. AMPure XP Beads (Beckman Coulter) were used to purify PCR products that were then tested for integrity on a 2200 TapeStation System (Agilent). After quantification of DNA concentration by QuBit dsDNA high-sensitivity assay (Invitrogen), samples were pooled and loaded onto an Illumina MiSeq. After demultiplexing, amplicon reads were analyzed for editing efficiency using CRISPResso2 (Clement et al., 2019). [00220] Off-target analyses. Deep amplicon sequencing (described above) was used to measure several important genes for potential off-target editing of ABE8e-SpRY and sgRNA6. First, potential editing of other CaMKII isoforms (α, β, and γ) was measured in human iPSCs after nucleofection of ABE components using the primers listed in Table S3. Using the cutting frequency determination (CFD) score of CRISPOR, the inventors identified the next top eight candidate off-target sites in the human genome (Table S4) and evaluated them in human iPSCs with the primers listed in Table S5 (Concordet & Haeussler, 2018). [00221] Besides CaMKIIδ, the inventors also measured potential editing of other CaMKII isoforms (α, β, and γ) in mouse hearts injected with AAV-ABE-sgRNA6. Since targeting CaMKII in organs other than heart may have potentially severe adverse side effects, the inventors tested for off-organ editing in the brain, which expresses all CaMKII isoforms, the tibialis anterior muscle (for CaMKIIδ), and the liver (for CaMKIIδ). Editing of CaMKIIδ was also analyzed in mice that were injected with a control virus encoding either half of the split adenine base editor (double N- or C-term AAV9) to test whether this was a true control and did not edit CaMKIIδ. [00222] The inventors reported the formal adenine to guanine editing for each adenine along the DNA sequences corresponding to sgRNA6. An allele frequency of 0.2% has previously been used as a cut-off to distinguish from unspecific background guanine signal (Clement et al., 2019). This cut-off is displayed in the graphs and adenines with a guanine level below this threshold are considered as not edited. [00223] Quantitative real-time PCR analysis. TRIzol (Thermo Fisher Scientific) and RNeasy Mini Kit (Qiagen) were used to isolate total RNA. Following reverse transcription with iScript Reverse Transcription Supermix (Bio-Rad), quantitative polymerase chain reaction (qPCR) was performed using KAPA PROBE FAST qPCR Kit - ROX Low (Roche). TaqMan Gene Expression Assays (all from Thermo Fisher Scientific) for CaMKIIβ (assay ID Hs00365799_m1), CaMKIIδ (assay ID Hs00943547_m1), and GAPDH (assay ID Hs99999905_m1) were performed using a QuantStudio™ 5 Real-Time PCR System (Applied Biosystems). Expression of CaMKIIβ and CaMKIIδ are reported as percentage of GAPDH. [00224] Differentiation of human iPSC into cardiomyocytes. At 70-80% confluency, iPSCs were differentiated into cardiomyocytes by subjecting them to CHIR99021 (Selleckchem) in RPMI supplemented with ascorbic acid (50 µg/mL) and B27 without insulin (RPMI/B27-) for 24 hours (day 0). After that, medium was replaced with RPMI/B27- for 2 days, before replacing it again with RPMI/B27- supplemented with WNT-C59 (Selleckchem). After another 2 days, medium was refreshed with RPMI/B27-. From day 7 onwards, iPSC- cardiomyocytes were cultured in RPMI with ascorbic acid (50 µg/mL) and B27 (RPMI/B27). Beginning on day 10, cells were maintained in RPMI without glucose and supplemented with 5 mM sodium DL-lactate and CDM3 supplement to metabolically select for cardiomyocytes. After 5 days, medium was replaced with RPMI/B27 and refreshed every 3 days. CMs were analyzed after day 30. For all experiments involving iPSC-derived cardiomyocytes, data were collected from at least three independent differentiations. [00225] Simulated ischemia/reperfusion in vitro. Simulated ischemia/reperfusion (IR) with a hypoxia chamber was used to challenge human iPSC-derived cardiomyocytes in vitro, as previously described (Zhang et al., 2021). Regular cardiomyocyte culture medium (RPMI/B27) was replaced by freshly made ischemia Esumi buffer (117 mM NaCl, 12 mM KCl, 0.9 mM CaCl ₂ , 0.49 mM MgCl ₂ , 4 mM HEPES, 20 mM sodium lactate, and 5.6 mM 2-deoxyglucose at pH 6.2) and cardiomyocytes were placed in a MIC-101 Modular Incubator Chamber at 37° C (Billups-Rothenberg). Cardiomyocytes were subjected to simulated ischemia (95% N ₂ and 5% CO ₂ ) for five hours. Meanwhile, control cardiomyocytes were exposed to normoxia control medium (137 mM NaCl, 3.8 mM KCl, 0.9 mM CaCl ₂ , 0.49 mM MgCl ₂ , 4 mM HEPES, and 5.6 mM D-glucose at pH 7.4). After five hours, ischemia and normoxia buffers were replaced with fresh culture medium (RPMI/B27). Cells were placed in a regular cell culture incubator for 14 hours reperfusion and were then analyzed. [00226] Western blot analysis. Western blot analysis was performed using either iPSC-derived cardiomyocytes or snap-frozen hearts that were pulverized with a tissue crusher. Proteins were isolated using RIPA buffer (Sigma-Aldrich) supplemented with protease- and phosphatase-inhibitors (Roche). Sonication with a Bioruptor Pico (Diagenode, 10 cycles of 30 s sonication on and 30 s off) was used to break genomic DNA. Samples were then centrifuged for 15 min at 10,000 x g at 4º C and supernatant was stored at -80º C. Protein concentration was measured with a BCA assay (Thermo Fisher Scientific) and equal amounts of protein were loaded on a Mini-PROTEAN® TGX™ gel (Bio-Rad). Proteins were transferred on a polyvinylidene fluoride membrane (Millipore), blocked in 5% milk in TBS- Tween 0.1% and incubated at 4º C overnight with the primary antibody: rabbit polyclonal anti- oxCaMKII (1:1,000, Sigma-Aldrich, catalog number 07-1387), rabbit polyclonal anti- pCaMKII (1:1,000, Invitrogen, catalog number PA5-37833), mouse monoclonal anti-CaMKII (1:1,000, BD Biosciences, catalog number 611293), rabbit polyclonal anti-pRyR2 (at serine 2814, 1:1,000, Badrilla, catalog number A010-31AP), rabbit polyclonal anti-RyR2 (1:1,000, Sigma-Aldrich, catalog number HPA020028), and mouse monoclonal anti-GAPDH (1:1,000, Sigma-Aldrich, catalog number MAB374). Secondary antibodies were HRP-conjugated goat anti-rabbit (1:10,000, Bio-Rad, catalog number 1706515) and HRP-conjugated goat anti- mouse (1:10,000, Bio-Rad, catalog number 1706516) and were incubated for one hour at room temperature. Immunodetection was done on a ChemiDoc MP Imaging System (Bio-Rad) using Western Blotting Luminol Reagent (Santa Cruz Biotechnology). Mean densitometric analysis was performed using ImageJ. [00227] Measurement of CaMKII activity. CaMKII activity assays were performed with iPSC-derived cardiomyocytes and with snap-frozen hearts that were pulverized with a tissue crusher. Proteins were isolated in 1% (v/v) Triton X-100, 20 mM Tris, 100 mM NaCl supplemented with protease- and phosphatase-inhibitors (Roche) at a pH of 7.4. After centrifugation for 15 min at 10,000 x g at 4º C, the supernatant was collected. Equal volumes were loaded to the CycLex® CaM-kinase II assay kit (MBL International Corporation) that was performed according to the manufacturer’s recommendations and absorbance at 450 nm was measured with a CLARIOstar microplate reader (BMG LABTECH). Some experiments were performed in presence of 1 μM of the CaMKII inhibitor myristoylated autocamtide-2 related inhibitory peptide (AIP, Sigma-Aldrich, diluted in Kinase Buffer of the CycLex® CaM- kinase II assay kit). A standard curve was generated using the CaM-kinase II Positive Control (MBL International Corporation). The measured CaMKII activity of each sample was then normalized to the protein concentration of the lysate (BCA assay, Thermo Fisher Scientific). [00228] Measurements of cellular Ca ²⁺ characteristics. Cellular Ca ²⁺ characteristics were assessed using epifluorescence microscopy. Human iPSC-derived cardiomyocytes were replated on a glass bottom microwell dish (MatTek Corporation) to a single cell density and were cultured for one week in RPMI/B27 to acclimate and reach a steady-state status. On the day of the experiment, cardiomyocytes were loaded with 5 μM Fura- 2 AM (20 min at 37º C, Invitrogen) and were mounted on an inverted microscope (Motic AE31E). Ca ²⁺ dynamics was measured using a fluorescence detection system (IonOptix) and Fura-2 fluorescence emission ratio was obtained by alternating excitation at 340 nm and 380 nm (switching rate 1,000 Hz). [00229] Before the measurement was started, cardiomyocytes were incubated for 15 min with Tyrode’s solution (140 mmol/l NaCl, 4 mmol/l KCl, 1 mmol/l MgCl ₂ , 10 mmol/l HEPES, 10 mmol/l Glucose, 1.25 mmol/l CaCl ₂ , pH=7.4) to ensure de-esterification of intracellular Fura-2 AM. Regular Ca ²⁺ transients were measured at a steady-state status under electrical field stimulation (1 Hz with a 5 ms pulse of 30 V). Ca ²⁺ transient characteristics and the occurrence of arrhythmias were analyzed using IonWizard 6.0 analysis software (IonOptix). [00230] Ischemia/reperfusion injury in adult mice. Male C57Bl6 wildtype mice (Charles River) were housed in a standard mouse facility with a regular 12-hour light/dark cycle and received standard chow (2916 Teklad Global). At 12 weeks of age, ischemia/reperfusion (IR) surgery was performed in mice anesthetized with Ketamine/Xylazine complex, intubated, and ventilated with a MiniVent mouse ventilator (Hugo Sachs Elektronik, 105 breaths per minute, 250 μL stroke volume). Using a rectal probe, mouse body temperature was monitored and kept close to 37.0° C. All surgeries were performed by the same experienced surgeon in a standardized manner. Thoracotomy was performed between the left fourth and fifth ribs, a 7-0 nylon suture was set under the left anterior descending coronary artery, and a non-traumatic occluder was put on the artery for 45 min of ischemia. The ligature was then released and the CRISPR-Cas9 components were injected straight to the heart into the area of injury. While eight mice were injected with a functional (N- and C-term) CRISPR-Cas9 editing system (IR+Edit), another eight mice received a non-functional control virus injection, containing either the double amount of the C- or N-term of the AAV9 (IR+Control Virus). All mice were injected with 7.5x10 ¹¹ vg/kg bodyweight of each N- and C-term AAV9, resulting in a total virus amount of 1.5x10 ¹² vg/kg bodyweight. The intracardiac injections (single bolus of 30 μL volume) were performed by the mouse surgeon, who was blinded to the content of liquid. Eight more mice were subjected to IR injury without any injection and another eight mice were subjected to 45 min open chest without IR and without injection (sham). After that, the chest was carefully closed in layers and the mice were allowed to recover. [00231] Virus production. Adeno-associated virus serotype-9 (AAV9) was produced by the Boston Children’s Hospital Viral Core. Using discontinuous iodixanol gradients (Cosmo Bio, AXS-1114542-5) AAV9 vectors were purified and then concentrated with a Millipore Amicon filter unit (UFC910008, 100 kDa). Quantitative real-time PCR assays were used to measure AAV9 titers. [00232] Transthoracic echocardiography. Cardiac function was assessed in conscious mice using two-dimensional transthoracic echocardiography (VisualSonics Vevo2100 imaging system). M-mode traces were acquired, and analysis is based on the average of three consecutive heart beats. Left ventricular end-diastolic (LVIDd) and end-systolic (LVIDs) internal diameter were measured in M-mode tracings. Fractional shortening (%) was calculated by [(LVIDd – LVIDs) / LVIDd] × 100. Heart rate was calculated based on the interval of three consecutive heart beats. Echocardiography was performed one week before the IR injury as well as 24 hours, one week, two weeks, and three weeks after the IR. Each echocardiography was performed and analyzed by the same experienced operator blinded to the study. [00233] Magnetic resonance imaging. Cardiac magnetic resonance imaging (MRI) was performed in mice by the University of Texas Southwestern Medical Center’s Advanced Imaging Research Center on a 7-tesla pre-clinical scanner (Bruker Biospec, Germany) using a 72 mm volume transmitter coil with a 2x2 phased array surface receiver coil. Mice were anesthetized by inhalation of 1.5–2.5% isoflurane. The animal’s ambient temperature was maintained at 28° C using a Small Rodent Air Heater System (SA Instruments, Stony Brook, NY). A self-gated gradient echo (IntraGate, Bruker Biospin) sequence was used to obtain cine images in the short axis plane. The following imaging parameters were used: TE/TR=3.9/10 ms; number of k-space lines per R-R=1; slice thickness=1 mm, number of averages=3; flip=15°; FOV=30×30 mm ² ; matrix=192×192; in-plane resolution=0.15×0.15 mm ³ . Five to six contiguous slices were acquired. Segment version 3.0 (segment.heiberg.se) was used to analyze cardiac cine images and left ventricular volumes as well as ejection fraction were calculated (Heiberg et al., 2010). Each MRI was performed and analyzed by the same experienced operator blinded to the study. [00234] RNA sequencing. Snap-frozen cardiac mouse samples were homogenized in TRIzol (Thermo Fisher Scientific) using a Precellys Evolution homogenizer (Bertin Instruments, 3 cycles x 20 s at 6,800 rpm). RNeasy Micro Kit (Qiagen) was used to isolate RNA, according to manufacturer’s recommendations. KAPA mRNA HyperPrep kit (Kapa Biosystems) was used according to the manufacturer's instructions to prepare the RNA sequencing libraries. Using an Illumina NextSeq500 sequencer, high output 75 cycles single- ended sequencing was performed by the University of Texas Southwestern Medical Center CRI Sequencing Facility. [00235] Analysis of RNA sequencing data. The FastQC tool (version 0.11.8) was used for quality control to determine low quality and adaptor portion of the reads for trimming. Trimmomatic (version 0.39) was used for read-trimming and trimmed reads were aligned to the mouse reference genome (mm10) using HiSAT2 (version 2.1.0, default settings). Count matrix for each sample was produced by counting aligned reads using featureCounts (version 1.6.2) and raw count matrix was used for differential gene expression analysis using DESeq package (version 1.38.0) in R (version 3.5.1). For the principal component analysis (PCA), the raw counts of all samples were normalized using the rlog function in R. The normalized values were then used as input for the prcomp function. The calculated PC1 and PC2 scores were visualized in a scatter plot using the ggplot2 package. Analysis of enriched gene sets (gene ontology terms) was performed using Metascape (/metascape.org/) with the upregulated or downregulated genes as input (Zhou et al., 2019). [00236] The average percentage of adenine (A) to inosine (I) editing among adenosines in the transcriptome-wide sequencing analysis was obtained by using a previously described strategy (Koblan et al., 2021). The percentage of editing in each sample was quantified using REDItools2. The inventors removed all nucleotides except adenosines and filtered the remaining adenosines with a read coverage of less than 10 or a read quality score below 25 to avoid errors due to a low sampling or sequencing quality. The percentage of the transcriptome-wide A-to-I editing was calculated by dividing the number of A-to-I conversions in each sample by the total number of adenosines in the inventors’ dataset after filtering. [00237] Histology and Immunohistochemistry. For routine histology, TUNEL, and immunohistochemistry, mouse hearts were dissected out and cleaned in phosphate-buffered saline (PBS) containing cardioplegic 0.2 M KCl for 5 minutes before fixating in 10% neutral-buffered formalin (Sigma-Aldrich) overnight at room temperature. Then, samples were dehydrated in 70% ethanol and embedded in paraffin. Transverse cross- sections 1,500 μm below the expected normoxic myocardium were used for analyses. Sections were mounted on slides and subjected to trichrome and picrosirius red staining and images were captured at 10x magnification on a BZ-X700 microscope (Keyence). The fibrotic tissue was quantified in ImageJ by dividing the collagen positive area by the total area of the cross- section. [00238] Terminal deoxynucleotidyltransferase-mediated UTP end label (TUNEL) staining for apoptotic cells and immunohistochemical staining for troponin I were done on the same section. Sections were deparaffinized in xylene, run to water through graded ethanol, and antigen retrieval was conducted for 20 min heating in 1 mM EDTA (pH 8.0). Sections were further treated with 0.3% Triton X-100 and interceding PBS washes were performed throughout the protocol, before blocking with 3% normal goat serum. Primary antibody was rabbit polyclonal anti-troponin I (1:100, Santa Cruz Biotechnology, catalog number H-170) and was incubated overnight at 4° C. Sections were subsequently incubated with the secondary Cy3-conjugated goat anti-rabbit antibody (1:50, Jackson ImmunoResearch, catalog number 111-165-144) for 30 min at room temperature. To conclude the troponin-I immunohistochemistry, linked antigen, primary, and secondary antibodies in the sections were crosslinked with 4% paraformaldehyde before being subjected to the DeadEnd™ Fluorometric TUNEL System (Promega) according to the manufacturer's recommendations. Sections were further incubated with Hoechst 33342 (1:5,000, Invitrogen, catalog number H3570) for 5 min at room temperature. A LSM 800 confocal microscope (Zeiss) was used to capture images. Apoptotic cells are reported as percentage of the total number of cells. [00239] Treadmill exhaustion test. Exercise performance was evaluated by using the Exer-3/6 rodent treadmill, as previously described (Columbus Instrument) (Wang et al., 2021). To test for potential long-term adverse effects of CaMKIIδ editing, the inventors analyzed mice 260 days after intraperitoneal injection of AAV9 (1.5x10 ¹⁴ vg/kg bodyweight of each N- and C-term) at P5 as well as non-injected littermates. Before the exhaustion test, all mice were acclimated to the treadmill by three 10 min sessions with a velocity set to 0, 5, and 10 m/min for the first, second, and third day, respectively. The treadmill was inclined to 10° and the electric shock grid at the rear end was turned on (frequency of 3 Hz, stimulation intensity of 10). For the treadmill exhaustion test, mice were first subjected to a warm-up of 10 m/min for 2 min. The inventors then set the velocity to 15 m/min that was accelerated at a rate of 0.6 m/min per minute until the mouse was exhausted. Exhaustion was defined by continuous standing for 5 s on the shock grid, which was evaluated by the same observer for all experiments. Each mouse was subjected to transthoracic echocardiography immediately after exhaustion. [00240] Statistics. Data are presented as mean ± standard error of the mean (SEM). Normal distribution was tested using Shapiro-Wilk normality test. Unpaired Student’s t test was used for variables that were normally distributed. For variables that were not normally distributed, the Mann-Whitney test was applied. For the comparison of more than two groups that were normally distributed, one-way ANOVA with Holm-Sidak’s post-hoc correction was used. Kruskal-Wallis test with Dunn’s post-hoc correction was applied for the comparison of more than two groups that were not normally distributed. Two-way ANOVA with Holm- Sidak’s post-hoc correction was used for the comparison of more than two groups and two different factors. Categorial data were analyzed using Fisher’s exact test. Statistical tests were performed in GraphPad Prism 9. Two-sided p-values below 0.05 were considered statistically significant (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Example 2 – Results [00241] Design of a gene editing strategy to ablate the oxidative activation sites of CaMKIIδ. CRISPR-Cas9 adenine base editing (ABE) allows the precise conversion of adenine to guanine nucleotides without introducing double-stranded DNA breaks (Liu & Olson, 2022; Chemello et al., 2021; Gaudelli et al., 2017; Komor et al., 2016; Koblan et al., 2018). The inventors reasoned that ABE could potentially render CaMKIIδ insensitive to oxidation activation by converting ATG to GTG codons and thereby replacing the oxidation- sensitive methionines with valines (Fig. 1A). Instead of using CRISPR technology to correct genetic mutations, the inventors used the technology to disrupt a pathological signaling pathway, offering a potential therapeutic approach for cardiac disease. [00242] To identify optimal CRISPR-Cas9 base editing components, the inventors used HEK293 cells to screen six different single guide RNAs (sgRNAs; Table S1) that covered the genomic region encoding methionines 281 (adenine at nucleotide position c.841) and 282 (adenine at nucleotide position c.844). The sgRNAs were tested with two adenine base editors, ABEmax and ABE8e, in which the engineered deaminases were fused to either SpCas9 nickase or its variant SpRY nickase (Richter et al., 2020; Koblan et al., 2018; Walton et al., 2020). Sanger sequencing revealed that sgRNA1 combined with ABE8e-SpCas9 had the highest efficiency for editing c.A841G (p.M281V), without editing c.A844 (p.M282). sgRNA6 combined with ABE8e-SpRY showed a broader editing window, editing c.A841G (p.M281V), c.A844G (p.M282V), and c.A848G (p.H283R; Figs. 5A-D and Table 6). The inventors validated the sgRNA1 + ABE8e-SpCas9 and sgRNA6 + ABE8e-SpRY editing strategies in human induced pluripotent stem cells (iPSCs) using nucleofection and observed the same editing pattern seen in HEK293 cells (Figs.1B-D). The inventors picked several iPSC clones to test whether exposure to sgRNA6 + ABE8e-SpRY resulted in a heterozygous or homozygous genotype. Sanger sequencing revealed that 75%, 17%, and 8% of the clones were homozygous, heterozygous, and wildtype, respectively (Fig.6A). [00243] Analysis of potential off-target editing in human iPSCs. The two oxidation-sensitive methionines of human CaMKIIδ are encoded by exon 11 of the CaMKIIδ gene, which shares 79% nucleotide homology with CaMKIIα and 76% nucleotide homology with CaMKIIγ. The sgRNA6 sequence shared 85% homology with CaMKIIα and CaMKIIγ (Fig. 6B). The inventors used deep amplicon sequencing to validate the specificity of ABE genomic editing of CaMKIIδ with sgRNA6 + ABE8e-SpRY. In human iPSCs, the inventors observed no genomic changes of the CaMKIIα or CaMKIIγ genes (Fig. 6C and D and Table 7). However, sgRNA6 has sequence identity with the human CaMKIIβ gene, and sequencing analysis showed the human CaMKIIβ gene was edited by sgRNA6. Fortunately, CaMKIIβ is not expressed in human cardiomyocytes, so genomic editing of the CaMKIIβ gene in the heart would be inconsequential (Figs.6E-F) (Zhang & Brown, 2004). To assess off-target editing, the inventors used CRISPOR to identify the top eight potential off-target sites (Table S4) (Concordet & Haeussler, 2018). Sequence analysis showed adenine to guanine editing only in the DAZL gene at the adenine base 13 nucleotides upstream from the protospacer adjacent motif (PAM; Fig. 6G and Tables 8 and 9). This edited site is located in an intronic region which is not transcribed and therefore should not have deleterious consequences (Concordet & Haeussler, 2018). All other adenines of the predicted top-eight potential off-target sites showed adenine to guanine editing of less than 0.2%, which is considered unspecific background (Clement et al., 2019). [00244] Functional analyses of CaMKIIδ edited human iPSC-derived cardiomyocytes. To investigate the physiological consequences of both editing patterns, the inventors generated three independent human homozygous iPSC lines with sgRNA1, sgRNA6, or no sgRNA (WT) and differentiated them to cardiomyocytes (iPSC-CMs) that were subjected to simulated IR injury using a hypoxia chamber. There was no difference in the amounts of CaMKII protein in WT or edited iPSC-CMs (Figs.7A-E). After IR, WT iPSC-CMs showed an increase in CaMKII oxidation, as measured by Western blot with an antibody that specifically recognizes oxidized CaMKII, whereas CaMKII oxidation was strongly reduced in sgRNA1 iPSC-CMs and sgRNA6 iPSC-CMs (Figs.1E-F; Fig.7A). WT iPSC-CMs showed a dramatic increase in CaMKII autophosphorylation and activity post-IR, which was both reduced in sgRNA1 and sgRNA6 edited iPSC-CMs (Figs. 1E, 1G, and 1H). In accordance with the changes in CaMKII activity, the inventors observed increased CaMKII-dependent phosphorylation of ryanodine receptor type 2 (RyR2) at serine 2814 in WT but not in sgRNA1 or sgRNA6 iPSC-CMs post-IR (Figs.1I-J; Figs. 7A-E). Function of iPSC-CMs was assessed by measuring cellular Ca ²⁺ transients using epifluorescence microscopy. After IR, WT iPSC- CMs showed an increase in diastolic Ca ²⁺ levels, a decrease in Ca ²⁺ transient amplitude, and arrhythmias (Figs. 1K-L; Figs. 8A-D). In contrast, iPSC-CMs edited with sgRNA1 and sgRNA6 were protected from deleterious Ca ²⁺ alterations post-IR. [00245] CaMKIIδ editing in mice subjected to IR injury. Since editing with sgRNA6 conferred greater protection to iPSC-CMs than with sgRNA1, the inventors used mouse-sgRNA6 (with 95% homology to human-sgRNA6) and ABE8e-SpRY for base editing to ablate the CaMKIIδ oxidative activation sites in vivo in 12-week-old male C57Bl6 mice (Fig.2A and Figs. 9A-C). The inventors packaged the ABE components in adeno-associated virus serotype-9 (AAV9) using a split-intein trans-splicing system to accommodate the large size of ABE8e and sgRNA6. AAV9 was chosen as the delivery system because it effectively infects the hearts of mice and large mammals (Chemello et al., 2021; Amoasii et al., 2018). To ensure cardiac specificity, the inventors used the cardiac troponin T (cTnT) promoter to drive ABE8e expression. After cardiac IR, AAV9 expressing sgRNA6 and ABE8e-SpRY (AAV- ABE-sgRNA6) was injected (7.5x10 ¹¹ viral genomes (vg)/kg of each component) directly into the area of cardiac injury (Fig.2A). Control mice were subjected to IR with either an injection of control AAV9 or no injection. Sham-treated mice were also subjected to 45 min open-chest surgery. Before IR, all mice exhibited normal cardiac function and similar fractional shortening between the groups, as measured by echocardiography (Fig.2B and Figs.10A-E). As expected, cardiac function decreased 24 hours after IR surgery to a similar extent in all groups (Figs. 11A-E). While cardiac function remained stable for the first week (Figs. 12A-E), after two weeks, mice administered AAV-ABE-sgRNA6 began to functionally recover, as assessed by echocardiography (Fig.2B and Figs.13A-E). This recovery time is consistent with a previous study showing that genomic editing begins within one week after AAV9 delivery of CRISPR- Cas9 components in vivo (Amoasii et al., 2019). Three weeks post-IR, AAV-ABE-sgRNA6 edited mice showed further cardiac improvement and attained a level of fractional shortening comparable to that of the sham-treated mice (Figs. 2B-C; Figs. 14A-D). In addition, left ventricular end-diastolic dilation, a hallmark feature of heart failure, was observed after IR in control mice but was not seen post-IR in mice injected with AAV-ABE-sgRNA6 (Fig. 2D). Furthermore, cardiac magnetic resonance imaging, performed in a subgroup of mice at four weeks post-IR, showed impaired cardiac function in control mice and rescue of cardiac function in mice receiving AAV-ABE-sgRNA6 editing components, similar to the echocardiography findings (Fig.2E, Figs.15A-B). [00246] Analysis of editing efficiency and potential off-target editing after in vivo ABE. Molecular analyses of heart tissue were performed at five weeks post-IR. Deep amplicon sequencing of DNA revealed an adenine to guanine editing efficiency of 7.6±0.2% (c.A841G, p.M281V), 7.5±0.2% (c.A844G, p.M282V), and 8.4±0.2% (c.A848G, p.H283R) of the genomic DNA, and 46.1±1.1% (c.A841G, p.M281V), 46.1±1.1% (c.A844G, p.M282V), and 46.6±1.0% (c.A848G, p.H283R) at the cDNA level (Fig.3A and Table 7). This difference can be explained since the majority of cardiac CaMKIIδ is expressed in cardiomyocytes (Uhlen et al., 2015), which is the only cell type targeted by a troponin T-driven editing system. Notably, the inventors detected a much higher editing efficiency at the anterior wall with 82.7±1.2% (c.A841G, p.M281V), 85.7±0.7% (c.A844G, p.M282V), and 85.8±1.2% (c.A848G, p.H283R) at the cDNA level (Figs. 3B-C). This indicates that both critical methionines were ablated in almost all cardiomyocytes in the injured area of the heart. No off- target editing of the other CaMKII isoforms (α, β, γ) was seen in the hearts of mice injected with AAV-ABE-sgRNA6, as determined by deep amplicon sequencing (Figs. 16A-B and Table 7). As expected, mouse hearts injected with control AAV9 showed no genomic editing in the CaMKIIδ gene. Since CaMKII is expressed in many different tissues (Uhlen et al., 2015), editing CaMKII in organs other than the heart may potentially cause severe adverse effects. Assessment of CaMKII editing in other tissues did not reveal genomic editing of any CaMKII isoforms in the brain, the tibialis anterior muscle, or the liver, validating the cardiac specificity of the cTnT promoter used in the inventors’ AAV9 editing system (Figs.16A-D). The inventors also detected no increase in transcriptome-wide adenine to inosine editing in post-IR mice injected with AAV-ABE-sgRNA6 (Fig.3D). [00247] Protein analysis showed a 4.4-fold increase in the amount of oxidized CaMKII in control mice post-IR. Oxidized CaMKII post-IR was normalized in the hearts of mice injected with AAV-ABE-sgRNA6 (Figs. 3E-F; Figs. 17A-E). The residual signal of oxidized CaMKII in post-IR mice injected with AAV-ABE-sgRNA6 may either be unedited and oxidized CaMKIIδ, oxidized CaMKIIγ, or unspecific background. Consistent with the amount of oxidized CaMKII, CaMKII autophosphorylation and activity were increased in control mice post-IR but not in post-IR mice injected with AAV-ABE-sgRNA6 (Fig. 3E and Figs.3G-H; Figs.17A-E). Moreover, the inventors found CaMKII-dependent phosphorylation of RyR2 to be increased in control mice post-IR but not in CaMKIIδ edited mice post-IR (Figs. 3I-J; Figs.17A-E). [00248] Mechanisms of cardioprotection and long-term effects conferred by CaMKIIδ editing in vivo. RNA sequencing of control and AAV-ABE-sgRNA6 edited hearts revealed three different types of transcriptomes by principal component analysis (Figs. 18A- B). Although the transcriptome changed after IR, no differences were detected between the two different control groups post-IR. However, hearts subjected to IR and CaMKIIδ editing had a transcriptome different from control WT mouse hearts and formed a third cluster. In total, the inventors identified 211 genes that were differentially expressed in mice subjected to IR with injection of control AAV9 compared to sham-treated mice (Fig.18B). Gene ontology analysis of the 163 genes upregulated in IR (with control AAV9) revealed pathways related to cardiac disease, while pathways associated with the 48 downregulated genes were mainly related to cardiac function (Figs.18C-D). Compared to mice treated with the control virus, the inventors found 101 upregulated and 108 downregulated genes in hearts of mice with edited CaMKIIδ (Fig. 3K). Analysis of gene ontology terms revealed that pathways related to cardiac performance and disease, which were dysregulated in control AAV9 mice post-IR, were rescued in CaMKIIδ edited mice post-IR (Figs.3L-M). [00249] The inventors found a dramatic increase in the percentage of apoptotic cells in TUNEL-stained heart sections of mice post-IR compared to heart sections of sham- treated mice (Figs. 4A-B). In contrast to the hearts of control mice post-IR, the number of apoptotic cells in CaMKIIδ edited mice was comparable to the hearts of sham-treated mice. The inventors also found a 2.7-fold increase in the area of fibrotic tissue in mice post-IR, while the CaMKIIδ edited mice were protected against fibrosis post-IR (Figs.4C-D; figs.19 and 16). They observed an increase in myocardial infiltration of inflammatory cells in mice post-IR, but this was not seen in hearts of CaMKIIδ edited mice (Fig.19). [00250] To test for potential long-term adverse effects of CaMKIIδ editing, the inventors analyzed mice 260 days after intraperitoneal injection of AAV-ABE-sgRNA6 at P5. Compared to non-injected littermates, they detected no difference in bodyweight (Figs. 21A- I). Since oxidized CaMKII has previously been linked to exercise performance (especially in skeletal muscle), the inventors challenged these mice with a treadmill exhaustion test (Wang et al., 2021). The inventors observed no difference in exercise performance, and immediate echocardiography after exhaustion revealed normal cardiac function in mice subjected to cardiac-specific CaMKIIδ editing 260 days earlier (Figs.21A-I). [00251] Table S1. Sequences of sgRNAs tested in this study. [00252] Table S2. Primers used for Sanger sequencing analyses.

[00253] Table S3. Primers for deep amplicon sequencing of CaMKIIα, β, γ, δ.

[00254] Table S4. Analysis of potential off target editing sites in the human genome predicted by CRISPOR. [00255] Table S5. Primers for deep amplicon sequencing of potential off target editing sites in the human genome. ^{F d} TCGTCGGCAGCGTCAGATGTGTATAAGAGACAGACCATTGCCATTCACCTCAT 74

Example 3 – Discussion [00256] CaMKIIδ inhibition has previously been proposed as a therapy for cardiac disease, and several CaMKII inhibitors have been tested in preclinical studies (Nassal et al., 2020; Pellicena & Schulman, 2014; Lebek et al., 2018). However, these CaMKII inhibitors face several challenges (Nassal et al., 2020), as some were reported to inhibit other ion channels (for example potassium channels) (Hegyi et al., 2015) and others showed small therapeutic benefit (Nassal et al., 2020; Pellicena & Schulman, 2014; Lebek et al., 2018). Specific CaMKIIδ inhibitors that are ATP-competitive inhibitors also inhibit other kinases with potential deleterious effects, and other inhibitors are not bioavailable or cell permeable (Nassal et al., 2020; Pellicena & Schulman, 2014). Another challenge in using CaMKIIδ inhibitors is that CaMKIIδ is ubiquitously expressed, and its global inhibition can have adverse effects in tissues other than the heart (Uhlen et al., 2015). Another clinical limitation of using CaMKIIδ inhibitors is the requirement for daily administration. Using the CRISPR-Cas9 ABE system to edit the genome provides a permanent change to the CaMKIIδ gene and overrides many of the above limitations. Incorporation of the cTnT promoter to restrict expression of the ABE components exclusively to the heart also prevents possible adverse consequences of CaMKIIδ inhibition in other tissues. Moreover, CRISPR-Cas9 gene editing is permanent, representing a “one and done” therapy (Karri et al., 2022). [00257] In patients, administration of CaMKIIδ editing components after a myocardial infarction could be achieved in conjunction with the standard of care in response to a heart attack. The first therapeutic step after a myocardial infarction is coronary angiography and revascularization of the infarct artery, which requires a catheter that could also be used to deliver CaMKIIδ editing components to the infarct artery or to the infarct area (Lawton et al., 2022). Prior to a first-in-human clinical trial, future studies are needed, including more analyses of the pharmacological profile, optimization of the viral dosage, more studies regarding the toxicity and safety of the treatment (such as potential immunogenicity of the base editor), and assessment of animal long-term survival. The inventors analyzed the top eight predicted sites in the human genome for potential off target editing, but a deeper analysis (Musunuru et al., 2021), especially after extended exposure to the base editor, will be required for formal regulatory review. It will also be necessary to analyze the interaction with other drugs and treatments as well as the effectiveness of CaMKIIδ editing compared to currently available heart failure medication. Further studies showing a benefit in larger animals such as pigs and non-human primates would also be an important step toward clinical advancement of this approach. [00258] CRISPR-Cas9 gene editing technology is typically used to correct specific genetic mutations before disease onset (Liu & Olson, 2022; Chemello et al., 2021; Richter et al., 2020; Amoasii et al., 2018; Amoasii et al., 2019; Koblan et al., 2021). Since the total number of patients carrying one specific mutation is usually low, the offered treatment affects only a limited group of patients. CRISPR-Cas9 gene has already been used to knock down wildtype PCSK9 gene in the liver as a strategy for hereditary familial hypercholesterolemia (Musunuru et al., 2021). This strategy is designed to ablate a detrimental pathway in the adult heart and thereby provide therapeutic benefits for already established heart disease. The concept of using CRISPR-Cas9 to block activation of deleterious pathways is also translatable to other signaling cascades in other human diseases. * * * [00259] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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