MONDAL ANUPAM (US)
ZHENG WEI (US)
CHEN YU HOLLY (US)
SWAROOP ANAND (US)
SWAROOP MANJU (US)
TAWA GREGORY (US)
PAPAL SAMANTHA (US)
LUO ZHIJI (US)
US5443505A | 1995-08-22 | |||
US5766242A | 1998-06-16 | |||
US0000207W | 2000-01-05 | |||
US0214279W | 2002-05-02 | |||
US6251090B1 | 2001-06-26 | |||
US6299895B1 | 2001-10-09 | |||
US6416777B1 | 2002-07-09 | |||
US6413540B1 | 2002-07-02 | |||
US0028187W | 2000-10-12 |
EVANS JWORMALD R., BRITISH JOURNAL OPHTHALMOLOGY, vol. 80, 1996, pages 9 - 14
KLEIN RKLEIN B E KLINTON K L P, OPHTHALMOLOGY, vol. 99, 1992, pages 933 - 943
VINGERLING J R, OPHTHALMOLOGY, vol. 102, 1995, pages 205 - 210
HAGEMAN G SMULLINS R F, MOL VIS, vol. 5, 1999, pages 28
S. M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
T. HIGUCHIV. STELLA: "A.C.S. Symposium Series", vol. 14, article "Pro-drugs as Novel Delivery Systems"
"Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
"GENBANK", Database accession no. NP_000274
AMBATI ET AL., INVEST. OPTHALMOL. VIS. SCI., vol. 41, 2000, pages 1186 - 1191
CHANG ET AL., HUM MOL GENET, vol. 15, 2006, pages 1847 - 57
CHEN ET AL., MOL VIS, vol. 22, 2016, pages 1077 - 1094
AKIMOTO ET AL., PROC NATL ACAD SCI USA, vol. 103, 2006, pages 3890 - 5
We claim: 1. A method of treating retinal degeneration in a subject, comprising administering to the subject a therapeutically effective amount of a compound thereby treating the retinal degeneration in the subject, wherein the compound is selected from a compound having a structure according to a formula selected from Formula I, II, or III or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof; or 3-(dibutylamino)-1- (1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride or another pharmaceutically acceptable salt, or a prodrug, solvate, hydrate, or tautomer thereof; wherein, (i) with reference to Formula I, R1 is heteroaliphatic; R2 is OR5, or NR6R7, wherein each of R5, R6, and R7 independently is selected from aliphatic, hydrogen, aromatic, or an organic functional group; R3 is selected from aliphatic, aromatic, acyl, or sulfonyl; R4 is selected from acyl, aliphatic, aromatic, or sulfonyl; and n is an integer selected from 0 to 4; (ii) with reference to Formula II, RA, is selected from halogen, heteroaliphatic, haloaliphatic, or an organic functional group; RB is aromatic; and each of RC and RD independently is selected from hydrogen, aliphatic, or heteroaliphatic; and m is an integer selected from 0 to 4; and (iii) with reference to Formula III, R’ is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or an organic functional group; each R’’ independently is selected from halogen, heteroaliphatic, or amino; each R’’’ independently is selected from halogen, heteroaliphatic, or amino; p is an integer selected from 0 to 4; q is an integer selected from 0 to 4; and r is an integer selected from 0 or 1. 2. The method of claim 1, wherein the subject has retinitis pigmentosa, LCA, Stargardt's macular dystrophy, cone-rod dystrophy, choroideremia or age-related macular degeneration. 3. The method of claim 1 or claim 2, wherein the compound is administered orally. 4. The method of claim 1 or claim 2, wherein the compound is administered locally to the eye of the subject. 5. The method of claim 4, wherein the compound is administered intravitreally in the eye of the subject. 6. The method of any one of claims 1-5, wherein the subject is human. 7. The method of any one of claims 1-6, wherein with the compound maintains thickness of a nuclear layer of photoreceptors in a retina of the eye of the subject. 8. The method of any one of claims 1-7, wherein the compound increases expression of an opsin in the retina of the subject. 9. The method of claims 8, wherein the photoreceptor opsin is a cone opsin, rhodopsin, or a phototransduction protein that comprises rod cyclic GMP phosphodiesterase 6β (PDE6β). 10. The method of any one of claims 1-9, wherein the compound increases the number of photoreceptor cells in the subject. 11. The method of any one of claims 1-10, further comprising evaluating the vision of the subject. 12. The method of claim 11, comprising performing electroretinography on the subject. 13. The method of any one of claims 1-12, wherein the compound has a structure according to any one of Formulas IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof 14. The method of any one of claims 1-13, wherein the compound has a structure according to Formula I, IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, wherein: R1 is alkoxy; R2 is -OR5, or -NR6R7, wherein each of R5, R6, and R7 independently is selected from alkyl, hydrogen, heteroaryl, or aryl; R3 and is selected from alkyl, heteroaryl, aryl, sulfonyl, or acyl; R4 is selected from acyl, alkyl, heteroaryl, aryl, or sulfonyl; and n is 0, 1, 2, 3, or 4. 15. The method of any one of claims 1-14, wherein the compound has a structure according to Formula I, IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, and wherein R4 is selected from 16. The method of any one of claims 1-15, wherein the compound is selected from or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. 17. The method of any one of claims 1-12, wherein the compound has a structure according to Formula IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof Formula IIA. 18. The method of any one of claims 1-12 or 17, wherein the compound has a structure according to Formula II or IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, wherein: each RA independently is selected from halogen, -OMe, -CN, or -CF3; RB is selected from aryl; aryl comprising one or more substituents selected from halogen, -CF3, -CN, -OH, alkyl, or alkoxy; heteroaryl; heteroaryl comprising one or more substituents selected from halogen, - CF3, -CN, -OH, alkyl, or alkoxy; each of RC and RD independently is selected from hydrogen, alkyl, or amino; and m is 0, 1, 2, 3, or 4. 19. The method according to any one of claims 1-12, 17, or 18, wherein the compound has a structure according to Formula II or IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, and RB is selected from 20. The method according to any one of claims 1-12, or 17-19, wherein the compound is , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof 21. The method according to any one of claims 1-12, wherein the compound has a structure according to Formulas IIIA-IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof 22. The method according to any one of claims 1-12 or 21, wherein the compound has a structure according to Formula III or IIIA-IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, and wherein R’ is selected from halo, -CN; -CF3; -OCF3; alkyl; heteroalkyl comprising one or more nitrogen atoms, one or more oxygen atoms, one or more sulfur atoms, or a combination thereof; or aminoaryl; R’’ is selected from halogen, alkoxy, or -NRa’Rb’, wherein each of Ra’ and Rb’ independently is selected from alkyl, heteroalkyl, benzyl, acyl, sulfonyl; R’’’ is selected from halogen, alkoxy, or -NRa’Rb’, wherein each of Ra’ and Rb’ independently is selected from alkyl, heteroalkyl, benzyl, acyl, or sulfonyl; p and q independently is an integer selected from 0, 1, 2, 3, or 4; and r is 0 or 1. 23. The method according to any one of claims 1-12, 21, or 22, wherein the compound has a structure according to Formula III or IIIA-IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, wherein R’ is selected from wherein R’’ and R’’’ independently is -NRa’Rb’, wherein one of Ra’ and Rb’ is H and the other is selected from . 24. The method according to any one of claims 1-12 or 21-23, wherein the compound is selected from a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. 25. The method of claim 1, wherein the compound is selected from 26. A composition, comprising a therapeutically effective amount of a compound according to any one of claims 1 or 13-25 for use in treating retinal degeneration in a subject. 27. The composition of claim 26, formulated for oral administration. 28. The composition of claim 27, wherein the composition is included in a dosage form. 29. The composition of claim 26, formulated for local administration to the eye. 30. The composition of claim 29, formulated for intravitreal administration. 31. The composition of any one of claims 26-30, further comprising a therapeutically acceptable excipient. 32. A composition, comprising a therapeutically effective amount of a compound for use in the method of any one of claims 1-25, wherein the compound is selected a compound having a structure according to a formula selected from Formula I, II, or III , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof; or 3-(dibutylamino)-1- (1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride or another pharmaceutically acceptable salt, or a prodrug, solvate, hydrate, or tautomer thereof; wherein, (i) with reference to Formula I, R1 is heteroaliphatic; R2 is OR5, or NR6R7, wherein each of R5, R6, and R7 independently is selected from aliphatic, hydrogen, aromatic, or an organic functional group; R3 is selected from aliphatic, aromatic, acyl, or sulfonyl; R4 is selected from acyl, aliphatic, aromatic, or sulfonyl; and n is an integer selected from 0 to 4; (ii) with reference to Formula II, RA, is selected from halogen, heteroaliphatic, haloaliphatic, or an organic functional group; RB is aromatic; and each of RC and RD independently is selected from hydrogen, aliphatic, or heteroaliphatic; and m is an integer selected from 0 to 4; and (iii) with reference to Formula III, R’ is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or an organic functional group; each R’’ independently is selected from halogen, heteroaliphatic, or amino; each R’’’ independently is selected from halogen, heteroaliphatic, or amino; p is an integer selected from 0 to 4; q is an integer selected from 0 to 4; and r is an integer selected from 0 or 1. 33. A compound for use as a medicament in a method for treating retinal degeneration in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound thereby treating the retinal degeneration in the subject, wherein the compound is selected from a compound having a structure according to a formula selected from Formula I, II, or III or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof; or 3-(dibutylamino)-1- (1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride or another pharmaceutically acceptable salt, or a prodrug, solvate, hydrate, or tautomer thereof; wherein, (i) with reference to Formula I, R1 is heteroaliphatic; R2 is OR5, or NR6R7, wherein each of R5, R6, and R7 independently is selected from aliphatic, hydrogen, aromatic, or an organic functional group; R3 is selected from aliphatic, aromatic, acyl, or sulfonyl; R4 is selected from acyl, aliphatic, aromatic, or sulfonyl; and n is an integer selected from 0 to 4; (ii) with reference to Formula II, RA, is selected from halogen, heteroaliphatic, haloaliphatic, or an organic functional group; RB is aromatic; and each of RC and RD independently is selected from hydrogen, aliphatic, or heteroaliphatic; and m is an integer selected from 0 to 4; and (iii) with reference to Formula III, R’ is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or an organic functional group; each R’’ independently is selected from halogen, heteroaliphatic, or amino; each R’’’ independently is selected from halogen, heteroaliphatic, or amino; p is an integer selected from 0 to 4; q is an integer selected from 0 to 4; and r is an integer selected from 0 or 1. 34. A compound for use in a method for treating retinal degeneration in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound thereby treating the retinal degeneration in the subject, wherein the compound is selected from a compound having a structure according to a formula selected from Formula I, II, or III or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof; or 3-(dibutylamino)-1- (1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride or another pharmaceutically acceptable salt, or a prodrug, solvate, hydrate, or tautomer thereof; wherein, (i) with reference to Formula I, R1 is heteroaliphatic; R2 is OR5, or NR6R7, wherein each of R5, R6, and R7 independently is selected from aliphatic, hydrogen, aromatic, or an organic functional group; R3 is selected from aliphatic, aromatic, acyl, or sulfonyl; R4 is selected from acyl, aliphatic, aromatic, or sulfonyl; and n is an integer selected from 0 to 4; (ii) with reference to Formula II, RA, is selected from halogen, heteroaliphatic, haloaliphatic, or an organic functional group; RB is aromatic; and each of RC and RD independently is selected from hydrogen, aliphatic, or heteroaliphatic; and m is an integer selected from 0 to 4; and (iii) with reference to Formula III, R’ is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or an organic functional group; each R’’ independently is selected from halogen, heteroaliphatic, or amino; each R’’’ independently is selected from halogen, heteroaliphatic, or amino; p is an integer selected from 0 to 4; q is an integer selected from 0 to 4; and r is an integer selected from 0 or 1. |
In some embodiments, the compound can be selected from any of the following, including a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof: methyl (1S,2R,3R,4aS,13bR,14aS)-2,11-dimethoxy-3-((3,4,5-trimethoxy benzoyl)oxy)- 1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]p yrido[1,2-b]isoquinoline-1- carboxylate (also referred to herein as “Reserpine” or “NCGC0091250”); methyl (1S,2R,3R,4aS,13bR,14aS)-2-methoxy-3-((3,4,5-trimethoxybenzo yl)oxy)- 1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]p yrido[1,2-b]isoquinoline-1- carboxylate; methyl (1S,2R,3R,4aS,13bR,14aS)-3-(((E)-3-(4-hydroxy-3- methoxyphenyl)acryloyl)oxy)-2,11-dimethoxy-1,2,3,4,4a,5,7,8, 13,13b,14,14a- dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carb oxylate (also referred to herein as “Rescimetol” or “NCGC00253604”); methyl (1S,2R,3R,4aS,13bR,14aS)-2,11-dimethoxy-3-(2-(4-methoxypheno xy)acetoxy)- 1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]p yrido[1,2-b]isoquinoline-1- carboxylate; methyl (1S,2R,3R,4aS,13bR,14aS)-2,11-dimethoxy-3-(((E)-3-(3,4,5- trimethoxyphenyl)acryloyl)oxy)-1,2,3,4,4a,5,7,8,13,13b,14,14 a- dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carb oxylate; methyl (1S,2R,3R,4aS,13bR,14aS)-3-((4-((ethoxycarbonyl)oxy)-3,5- dimethoxybenzoyl)oxy)-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b ,14,14a- dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carb oxylate; methyl (1S,2R,3R,4aS,13bR,14aS)-3-hydroxy-2,11-dimethoxy- 1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]p yrido[1,2-b]isoquinoline-1- carboxylate; (1S,2R,3R,4aS,13bR,14aS)-3-hydroxy-2,11-dimethoxy-1,2,3,4,4a ,5,7,8,13,13b,14,14a- dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carb oxylic acid; methyl 2,11-dimethoxy-3-((3,4,5-trimethoxybenzoyl)oxy)- 1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]p yrido[1,2-b]isoquinoline-1- carboxylate; methyl 2-methoxy-3-((3,4,5-trimethoxybenzoyl)oxy)-1,2,3,4,4a,5,7,8, 13,13b,14,14a- dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carb oxylate; methyl (E)-3-((3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)-2,11-dime thoxy- 1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]p yrido[1,2-b]isoquinoline-1- carboxylate; methyl 2,11-dimethoxy-3-(2-(4-methoxyphenoxy)acetoxy)- 1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]p yrido[1,2-b]isoquinoline-1- carboxylate; methyl (E)-2,11-dimethoxy-3-((3-(3,4,5-trimethoxyphenyl)acryloyl)ox y)- 1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]p yrido[1,2-b]isoquinoline-1- carboxylate; methyl 3-((4-((ethoxycarbonyl)oxy)-3,5-dimethoxybenzoyl)oxy)-2,11-d imethoxy- 1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]p yrido[1,2-b]isoquinoline-1- carboxylate; methyl 3-hydroxy-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a- dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carb oxylate; or 3-hydroxy-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a- dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carb oxylic acid. In particular embodiments of Formula II (or Formula IIA, below), the following variable recitations can apply: each R A independently can be selected from halogen (e.g., Cl, F, Br, or I), -OMe, -CN, or -CF 3 ; R B can be selected from aryl (e.g., C 6-10 aryl); aryl (e.g., C 6-10 aryl) comprising one or more substituents selected from halogen, -CF 3 , -CN, -OH, alkyl (e.g., C 1-6 alkyl), alkoxy (e.g., C 1-6 alkoxy); heteroaryl (e.g., C 4-10 heteroaryl); heteroaryl (e.g., C 4-10 heteroaryl) comprising one or more substituents selected from halogen, -CF 3 , -CN, -OH, alkyl (e.g., C 1-6 alkyl), alkoxy (e.g., C 1-6 alkoxy); each of R C and R D independently can be selected from hydrogen, alkyl (e.g., C 1-12 alkyl or C 3- 8 cycloalkyl), amino (e.g., C 1-12 alkylaminoalkyl, such as N,N-diethylaminobutanyl; or C 3- 8 cycloalkylaminoalkyl), or R C and R D can join together to form a four-, five-, six-, or seven-membered heterocylic ring system, including aromatic and non-aromatic versions thereof, along with the nitrogen atom to which they are bound; and m is 0, 1, 2, 3, or 4. In some embodiments, the compound embodiments of Formula II can further have a structure according to Formula IIA, including a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. Formula IIA In some additional embodiments of any of Formulas II or IIA, R B can be selected from any of the following groups:
In representative embodiments, m is 2 and each R A independently is a halogen (e.g., Cl), R B is not present or is a bi-thiophene group, and one of R C and R D is hydrogen and the other is N,N-diethylaminobutanyl. In particular embodiments, the compound is N1-(3-([2,2'-bithiophen]-5-yl)-6,7-dichloroquinoxalin-2-yl)- N4,N4-diethylbutane-1,4-diamine (also referred to herein as “NCGC00263128”) or any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. In particular embodiments of Formula III (or any one of Formulas IIIA-IIID), the following variable recitations can apply: R’, when present, can be selected from halo, -CN, -CF 3 , -OCF 3 , alkyl (e.g., C 1-12 alkyl), heteroalkyl (e.g., C 1-12 heteroalkyl comprising one or more nitrogen atoms, one or more oxygen atoms, one or more sulfur atoms, or a combination thereof and including cyclic and acyclic versions thereof), aminoaryl (e.g., - NR a’ -aryl or -NR a’ -aryl comprising one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , amino, heteroalkyl, amide, or sulfonamide); R’’, when present, can be selected from halogen, alkoxy, or -NR a’ R b’ , wherein each of R a’ and R b’ independently is selected from alkyl (e.g., C 1-12 alkyl), heteroalkyl (e.g., C 1-12 heteroalkyl), benzyl (e.g., - CH 2 aromatic or -CH 2 aromatic comprising one or more substituents selected from alkoxy, halogen, or amide), acyl (e.g., -C(O)alkyl, -C(O)alkenyl, -C(O)heteroalkyl, -C(O)aromatic, -C(O)aromatic comprising one or more substituents selected from alkyl, halogen, -CF 3 , -OCF 3 , or -CN), sulfonyl (e.g., -SO2R a , wherein R a is selected from hydrogen, alkyl, aromatic, aromatic comprising one or more substituents selected from alkyl, amide, or alkoxy); R’’’, when present, can be selected from halogen, alkoxy, or -NR a’ R b’ , wherein each of R a’ and R b’ independently is selected from alkyl (e.g., C 1-12 alkyl), heteroalkyl (e.g., C 1-12 heteroalkyl), benzyl (e.g., -CH 2 aromatic or -CH 2 aromatic comprising one or more substituents selected from alkoxy, halogen, or amide), acyl (e.g., -C(O)alkyl, -C(O)alkenyl, -C(O)heteralkyl, -C(O)aromatic, -C(O)aromatic comprising one or more substituents selected from alkyl, halogen, -CF 3 , -OCF 3 , or -CN), sulfonyl (e.g., -SO 2 R a , wherein R a is selected from hydrogen, alkyl, aromatic, aromatic comprising one or more substituents selected from alkyl, amide, or alkoxy); each of p and q independently is an integer selected from 0, 1, 2, 3, or 4; and r is 0 or 1. In some additional embodiments, R’ is present, R’’ is present, and R’’’ is not present and r is 0. In some other embodiments, each of R’, R’’, and R’’’ is present and R’’ and R’’’ are the same. In yet some additional embodiments, each of R’’ and R’’’ is present and R’ is not present. In yet some additional embodiments, R’ is present and neither of R’’ or R’’’ is present and in some such embodiments, r can be 1 and the resulting ring can be saturated. In particular embodiments, each of R’’ and R’’’ can be the same or different. Exemplary formulas illustrated at least certain of these options are illustrated below. In some additional embodiments of any of Formulas IIIA-IIID, R ’ can be selected from any of the following groups:
. In embodiments wherein R’’ and/or R’’’ is -NR a’ R b’ , each of R a’ and/or R b’ can be selected from any of the following groups, as well as hydrogen:
. In representative embodiments, R’ is heteroalkyl, R’’ and R’’’ are present and are Cl and OMe, respectively. In particular embodiments, compounds of Formula III are selected from the following, including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof.
In some embodiments, the compound can be selected from any of the following: N4-(6-chloro-2-methoxyacridin-9-yl)-N1,N1-diethylpentane-1,4 -diamine; N,N'-(piperazine-1,4-diylbis(propane-3,1-diyl))bis(6-chloro- 2-methoxyacridin-9- amine); N4-(6-chloro-2-methoxyacridin-9-yl)-N1,N1-diethylpentane-1,4 -diamine dihydrochloride dihydrate (also referred to herein as “Quinacrine dihydrochloride dihydrate” or “NCGC0015874”); N,N'-(piperazine-1,4-diylbis(propane-3,1-diyl))bis(6-chloro- 2-methoxyacridin-9- amine); N1,N7-bis(1,2,3,4-tetrahydroacridin-9-yl)heptane-1,7-diamine ; N4-(7-chloroquinolin-4-yl)-N1,N1-diethylpentane-1,4-diamine (also referred to herein as “chloroquine”); 2-((4-((7-chloroquinolin-4-yl)amino)pentyl)(ethyl)amino)etha n-1-ol (also referred to herein as “hydroxychloroquine”); 1-((2-((2-((7-chloroquinolin-4-yl)amino)ethyl)(methyl)amino) ethyl)amino)-4-methyl- 9H-thioxanthen-9-one (also referred to herein as “ROC-325”); acridine-3,6-diamine; acridine-3,6-diamine hemisulfate (also referred to herein as “Proflavine hemisulfate”); 6-chloro-2-methoxy-9-(2-methoxyethoxy)acridine; N1-(7-chloroquinolin-4-yl)-N2-(2-((7-chloroquinolin-4-yl)ami no)ethyl)ethane-1,2- diamine (also referred to herein as “Lys05”); or 6-chloro-2-methoxy-9-(piperidin-4-yloxy)acridine. In an independent embodiment, the compound can be 3-(dibutylamino)-1-(1,3-dichloro-6- (trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride (or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof), which has a structure: . In another independent embodiment, the compound can be N-[3-[[5-cyclopropyl-2-[(2-methyl-3,4- dihydro-1H-isoquinolin-6-yl)amino]pyrimidin-4-yl]amino]propy l]cyclobutanecarboxamide (or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof), which has a structure: . IV. Method of Making Compound Embodiments Method embodiments for making the compound embodiments of the present disclosure also are described. Exemplary method embodiments are described in the Examples of the present disclosure. In some embodiments, a method for making a compound according to Formula I can be made as described below. In some embodiments for making compounds of Formula I, methyl (1S,2R,3R,4aS,13bR,14aS)-3- hydroxy-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodeca hydroindolo[2',3':3,4]pyrido[1,2- b]isoquinoline-1-carboxylate can be used as a starting material (compound 100 in Scheme 1 below). In particular embodiments, an R 4 group can be installed on this starting compound using any of the following method embodiments. Any such methods further can be used to provide an R 3 group as described above for any of Formulas I, and IA-IE. In some embodiments, certain R 4 groups can be installed using Williamson ether synthesis from the reaction of alkyl halide with 100 under basic conditions as illustrated in Scheme 1, thereby providing product 102. Additional embodiments are provided below and representative methods are described in the Examples section. Sc e e In other embodiments, certain R 4 groups can be installed by reaction of 100 with a corresponding acyl halide or carboxylic acid as illustrated in Schemes 1A and 1B, respectively, thereby providing product 104. In yet other embodiments, certain R 4 groups can be installed by reaction of 100 with a corresponding sulfonyl chloride as illustrated in Scheme 1C, to thereby provide product 106. In some embodiments, compounds of Formula I comprising different R 2 groups (different from the methyl ester groups illustrated in Schemes 1 and 1A-1C) above can be made according to the following method embodiments illustrated in Scheme 1D, providing products 110 or 112. Also disclosed are method embodiments for making compounds represented by Formula II (and/or Formula IIA). In such embodiments, the method can comprise using a starting material 200, illustrated in Scheme 2 below, and coupling it with a corresponding palladium coupling reagent 202, which provides the R B group. While Scheme 2 illustrates a palladium-based coupling reaction using a boronic acid coupling partner (202), other coupling partners can be used, including those suitable for a Stille-based coupling (e.g., R B Sn(Bu)4, wherein R B can be selected from R B groups described in the definitions section) or a Negishi- based coupling (e.g., R B ZnX’, wherein R B can be selected from R B groups described in the definitions section and X’ can be halogen, triflate, ester, or the like). Additional embodiments are provided below and representative methods are described in the Examples section. In some embodiments, the method can comprise steps like those outlined in Scheme 2A, wherein X’’ can be CH or N (or an oxidized form thereof) and Y can be selected from aromatic (e.g., aryl or heteroaryl); aromatic (e.g., aryl or heteroaryl) comprising one or more substituents selected from halogen, - CN, alkoxy, -OCF 3 ; or aliphatic (e.g., cyclic aliphatic). Also disclosed are method embodiments for making compounds represented by Formula III (and/or Formulas IIIA-IIID). In such embodiments, the method can comprise reacting a precursor compound 300 (wherein Z is a halogen, such as chloro) with a suitable coupling component under suitable coupling conditions to provide product 302; or reacting a precursor compound 304 (wherein each of Z’ and Z’’ independently can be an amine or a hydroxyl group) with a suitable coupling component under suitable coupling conditions to provide product 306. Additional embodiments are provided below and representative methods are described in the Examples section. In some embodiments, the method can comprise steps like those outlined in Scheme 3A, wherein the R group of the RONa reagent can be alkyl or heteroalkyl; each Y’ can be selected from amino, heteroaliphatic, amide, or sulfonamide; and m’ is an integer selected from 0 to 5.
Scheme 3A In some embodiments, the method can comprise steps like those outlined in Scheme 3B, which comprise using starting material 314 (wherein the starting material comprises at least one hydrogen atom bound to each of the illustrated amine groups in addition to any R a’ or R b’ group) to which two of the same or different acyl and/or sulfonyl groups can be coupled using the corresponding acyl or sulfonyl coupling reagent (e.g., an acyl halide and/or a sulfonyl halide). With reference to Scheme 3B, at least one of the R a’ or R b’ groups attached to each amine of product 316 is an acyl group or a sulfonyl group. Symmetric versions of product 316 can be made, wherein each NR a’ R b’ group is the same; or asymmetric versions of product 316 can be made, wherein each NR a’ R b’ group is different. Scheme 3B In yet some additional embodiments, the method can comprise steps like those outlined in Scheme 3C, wherein starting material 314 is converted to product 316 using a sequence of protection, addition, and deprotection steps. Such embodiments can be used in certain examples to provide compounds wherein the amine nitrogen is bound to at least one aliphatic, heteroaliphatic, haloaliphatic, or aromatic group. Scheme 3C V. Method of Use Method embodiments are disclosed herein for treating and/or preventing retinal degeneration in a subject. The method embodiments can include selecting a subject with retinal degeneration, or a subject that is of risk for retinal degeneration. Generally, a therapeutically effective amount of a compound as disclosed herein is administered. In some embodiments, the compound can be 3-(dibutylamino)-1-(1,3-dichloro-6- (trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, or another pharmaceutically acceptable salt, prodrug, solvate, hydrate, and/or tautomer of 3-(dibutylamino)-1-(1,3-dichloro-6- (trifluoromethyl)phenanthren-9-yl)propan-1-ol. In additional embodiments, the compound can have a structure according one of Formulas I, II, or III, or any of the compounds disclosed herein, including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. This administration is sufficient to treat, inhibit and/or prevent retinal degeneration. In some embodiments, the subject has ongoing photoreceptor degeneration. In further embodiments, the method treats retinal degeneration in the subject. Various eye conditions may be treated or prevented by using compound embodiments disclosed herein. The conditions include retinal diseases or disorders generally associated with retinal dysfunction or degradation, retinal injury, and/or loss of retinal pigment epithelium. The disclosed methods are of use for treating a retinal degenerative disease, retinal (or retinal pigment) epithelium dysfunction, retinal degradation, retinal (or retinal pigment) epithelial damage. The disclosed methods are also of use for treating loss of retinal pigment epithelium. The methods include administering, such as locally administering, compound embodiments (or a composition thereof) to the eye of the subject. In some embodiments the retina degenerative disease is Stargardt's macular dystrophy, retinitis pigmentosa, age related macular degeneration, diabetic retinopathy, Leber congenital amaurosis (LCA), late- onset retinal degeneration, hereditary macular or acquired retinal degeneration, choroideremia, Best disease, Sorsby’s fundus dystrophy, gyrate atrophy, choroideremia, pattern dystrophy, or cone-rod dystrophy. In a specific non-limiting example, the subject has retinitis pigmentosa, LCA, Stargardt's macular dystrophy, cone-rod dystrophy, choroideremia, or age-related macular degeneration. In some embodiments, the method can include selecting a subject for treatment. In some embodiments, the method can include selecting a subject with Stargardt's macular dystrophy, retinitis pigmentosa, age related macular degeneration, diabetic retinopathy, Leber congenital amaurosis, late-onset retinal degeneration, hereditary macular or acquired retinal degeneration, choroideremia, Best disease, Sorsby’s fundus dystrophy, gyrate atrophy, choroideremia, pattern dystrophy, or cone-rod dystrophy. In a specific non-limiting example, the subject has retinitis pigmentosa, LCA, Stargardt's macular dystrophy, cone-rod dystrophy, choroideremia or age-related macular degeneration. Thus, the method can include selecting a subject with retinal degeneration, such as, but not limited to, a subject with retinitis pigmentosa, LCA, Stargardt's macular dystrophy, cone-rod dystrophy, choroideremia or age-related macular degeneration. In additional embodiments, subject can have diabetic retinopathy. The methods can include selecting a subject with diabetic retinopathy, or a subject at risk for diabetic retinopathy, such as a diabetic subject. Following selection, the subject is administered an effective amount of one or more compound embodiments as disclosed herein, including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. In certain embodiments, the presently disclosed methods embodiments can be used to treat any type of retinitis pigmentosa. In some embodiments, the retinitis pigmentosa is caused by mutations in the rhodopsin gene, the peripherin gene, and/or other genes expressed in the rod. The retinitis pigmentosa can be the result of a genetic condition inherited in an autosomal dominant, autosomal recessive or X-linked manner. The X-linked retinitis pigmentosa can be recessive, affecting males, or dominant, so that it affects males and females. The retinitis pigmentosa can be associated with rod-cone retinal degenerations present with central macular pigmentary changes (bull's eye maculopathy). The retinitis pigmentosa can be choroideremia, which is an X-linked recessive retinal degenerative disease. Generally, the retinitis pigmentosa (RP) is characterized by the progressive loss of photoreceptor cells. In additional embodiments, the presently disclosed methods can be used to prevent or treat age- related macular degeneration (AMD). In some embodiments, the subject has atrophic AMD (also called “dry” AMD), wherein the subject has symptomatic central vision loss due to retinal atrophy. In other embodiments, the subject has wet AMD. In further embodiments, the disclosed methods are of use to treat a subject with LCA. In more embodiments the disclosed methods are of use to LCA that has a defect in the CEP290 protein, and thus may have defects in trafficking of ciliary proteins. In yet other embodiments the subject has Stargardt's macular dystrophy. In more embodiments, the subject has cone-rod dystrophy. In a further embodiment, the subject has choroideremia. Diagnosis can utilize tests which examine the fundus of the eye and/or evaluate the visual field. These include electroretinogram, fluorangiography, and visual examination. The fundus of the eye examination aims to evaluate the condition of the retina and to evaluate for the presence of the characteristic pigment spots on the retinal surface. Examination of the visual field makes possible to evaluate the sensitivity of the various parts of the retina to light stimuli. An electroretinogram (ERG) can be used, which records the electrical activity of the retina in response to particular light stimuli and allows distinct valuations of the functionality of the two different types of photoreceptors (e.g., cone cells and rod cells). Combinations of the compounds can be used, including those combinations that act synergistically. Thus, in any of the disclosed methods, 2, 3, 4 or more compounds can be administered. In some embodiments, the compound is administered for 10, 15, 20, 25, or 30 days. In further embodiments, the compound is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. In additional embodiments, the compound can be administered for up to six months, or one year, two years, three years, or longer. In some examples, the compound can be administered daily, daily every other day, every three days, or weekly for the specified time period. A sustained release formulation, such as a compound-releasing drug depot or sustained release implant or device, can also be used. In some examples, the compound is administered daily. Systemic modes of administration include oral and parenteral routes. Parenteral routes include, by way of example, intravenous, intraarterial, intramuscular, intradermal, subcutaneous, intranasal and intraperitoneal routes. Compounds administered systemically may be modified or formulated to target the components to the eye, such as, but not limited to, intra-vitreal administration. In other embodiments, the compound is administered orally. A suitable oral formulation of a compound is, for example, a tablet or capsule, preferably a tablet containing, for example, about 10, 20, 30 or 40 mg/kg, of the compound. In some embodiments, the compound can be administered at a dose in the range of about 20 mg/kg to about 160 mg/kg per day, such as about 20 mg/kg to about 80 mg/kg, for example, about 20 mg/kg to about 40 mg/kg, either as a single dose or as divided doses. In a specific non-limiting example, this dose is administered daily. In other embodiments, the compound is administered orally at a dose of about 10 mg/kg to about 80 mg/kg. In other embodiments, a compound is administered orally at a dose of about 40 mg/kg to about 80 mg/kg. In some examples, a compound is administered orally at a dose of about 40, 45, 50, 55, 60, 65, 70, 75 or 80 mg/kg. In specific non-limiting examples, this dose is administered daily. In further embodiments, for humans, the compound is administered orally at a dose of about 0.8 mg/kg to about 6.5 mg/kg daily (≈10mg/kg/day, approximately equivalent to a 0.81 mg/kg/day dose in an adult human). In some non-limiting examples, the compound is administered orally at a dose of about 3.2 mg/kg to about 6.5 mg per kg daily. Suitable doses include, but are not limited to, about 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg.1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2 mg/kg, 2.1 mg/kg, 2.2 mg/kg, 2.3 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.7 mg/kg, 2.8 mg/kg, 2.9 mg/kg, 3 mg/kg, 3.1 mg/kg, 3.2 mg/kg, 3.3 mg/kg, 3.4 mg/kg, 3.5 mg/kg, 3.6 mg/kg, 3.7 mg/kg, 3.8 mg/kg, 3.9 mg/kg, 4.0 mg/kg, 4.1 mg/kg, 4.2 mg/kg, 4.3 mg/kg, 4,4 mg/kg, 4.5 mg/kg, 4.6 mg/kg, 4.7 mg/kg, 4.8 mg/kg, 4.9 mg/kg, 5.0 mg/kg, 5.1 mg/kg, 5.2 mg/kg, 5.3 mg/kg, 5.4 mg/kg, 5.5 mg/kg, 5.;6 mg/kg, 5.7 mg/kg, 5.8 mg/kg, 4.9 mg/kg, 6.0 mg/kg, 6.1 mg/kg, 6.2 mg/kg, 6.3 mg/kg, 6.4 mg/kg and 6.5 mg/kg. The compound can be formulated for administration in any oral formulation, including solid or liquid formulations. The compound can be administered daily. In one non-limiting example, the compound is administered orally at a dose of about 40 mg/kg to about 80 mg/kg daily for a minimum of 1, 23, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. In other non-limiting examples, the compound is administered orally at a dose of about 0.8 mg/kg to about 6.5 mg/kg daily for a minimum of 1, 23, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. In additional embodiments, the compound can be administered orally at a dose of about 0.8 mg/kg to about 6.5 mg/kg daily for up to six months, or one year, two years, three years, or longer. In some examples, the compound can be administered orally and daily, daily every other day, every three days, or weekly, for the specified time period. In some examples, the compound is administered daily and orally. In some non-limiting examples, the compound is administered orally at a dose of about 40 mg/kg to about 80 mg/kg daily for at least 3 months, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. In further non-limiting examples, the compound is administered orally at a dose of about 0.8 mg/kg to about 6.5 mg/kg daily for at least 3 months, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. The compound can be administered locally to the eye. Local modes of administration include, by way of example, intraocular, intraorbital, subconjunctival, sub-Tenon’s, subretinal or transscleral routes. In an embodiment, significantly smaller amounts of the components (compared with systemic approaches) may exert an effect when administered locally (for example, intravitreally) compared to when administered systemically (for example, intravenously). In one embodiment, the compound is delivered subretinally, e.g., by subretinal injection. Subretinal injections may be made directly into the macular, e.g., submacular injection. Exemplary methods include intraocular injection (e.g., retrobulbar, subretinal, submacular, intravitreal and intrachoridal), iontophoresis, eye drops, and intraocular implantation (e.g., intravitreal, sub- Tenons and sub-conjunctival). In one embodiment, the system disclosed herein is delivered by intravitreal injection. Intravitreal injection has a relatively low risk of retinal detachment. Methods for administration of agents to the eye are known in the medical arts and can be used to administer components described herein. Administration may be provided as a single administration, a periodic bolus, or as continuous infusion. In some embodiments, administration is from an internal reservoir (for example, from an implant disposed at an intra- or extra-ocular location – see, for example, U.S. Pat. Nos.5,443,505 and 5,766,242, the relevant portion of which is incorporated herein by reference) or from an external reservoir (for example, from an intravenous bag). Components can be administered by continuous release for a particular period from a sustained release drug delivery device immobilized to an inner wall of the eye or via targeted transscleral controlled release into the choroid (see, for example, PCT/US00/00207, PCT/US02/14279, Ambati et al., Invest. Opthalmol. Vis. Sci.41:1181-1185, 2000, and Ambati et al., Invest. Opthalmol. Vis. Sci. 41:1186-1191, 2000, the relevant portion of which is incorporated herein by reference). A variety of devices suitable for administering components locally to the inside of the eye are known in the art and can be selected for use in the present disclosure. See, for example, U.S. Patent No.6,251,090, U.S. Patent No. 6,299,895, U.S. Patent No.6,416,777, U.S. Patent No.6,413,540, and PCT Application No. PCT/US00/28187, the relevant portions of which are incorporated herein by reference. Dosage treatment may be a single dose schedule or a multiple dose schedule to ultimately deliver the amount specified above. The doses can be intermittent. Moreover, the subject may be administered as many doses as appropriate. In some embodiments, the subject is administered the compound prior to the onset of a condition. Individual doses are typically not less than an amount required to produce a measurable effect on the subject and may be determined based on the pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion ("ADME") of the subject composition or its by-products, and thus based on the disposition of the composition within the subject. This includes consideration of the route of administration as well as dosage amount, which can be adjusted for local and systemic (for example, oral) applications. Effective amounts of dose and/or dose regimen can readily be determined empirically from preclinical assays, from safety and escalation and dose range trials, individual clinician-patient relationships, as well as in vitro and in vivo assays. Generally, these assays will evaluate retinal degeneration, or expression of a biological component (cytokine, specific inflammatory cell, microglia, etc.) that affects retinal degeneration. In some embodiments, the dose can be an in vivo dose that corresponds to (i) an in vitro intermittent high dose of 20 ^M or 30 ^M or (ii) an in vitro continual lose dose of 10 ^M as administered in a CEP290-LCA in vitro assay used to determine compound efficacy in improving rhodopsin staining and/or ciliary axoneme growth. In some embodiments, the subject method results in a therapeutic benefit, such as preventing the development of retinal degeneration, halting the progression of a retinal degeneration, and/or reversing the progression of a retinal degeneration. The subject can have any form of retinal degeneration, as disclosed above. In some embodiments, the method includes the step of detecting that a therapeutic benefit has been achieved. Measures of therapeutic efficacy will be applicable to the particular disease being modified and a person having at least ordinary skill in the art, with the benefit of the present disclosure, will recognize the appropriate detection methods to use to measure therapeutic efficacy. In further embodiments, the compound embodiments disclosed herein (including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof) can increase the number of photoreceptors in the retina, as compared to a control. In yet other embodiments treatment with the compound embodiments disclosed herein (including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof) can maintain the thickness of the nuclear layer of photoreceptors in the retina over time. In more embodiments, the compound embodiments disclosed herein (including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof) can increase expression of a phototransduction protein, such as an opsin, rhodopsin, and/or rod cyclic GMP phosphodiesterase 6β (PDE6β), as compared to a control. In some embodiments, the compound embodiments disclosed herein (including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof) can increase rhodopsin and/or S-opsin expression, as compared to a control. In more embodiments, the compound embodiments disclosed herein (including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof) can increase a phototransduction protein, such as (but not limited to) a photoreceptor, as compared to a control. In yet additional embodiments, the compound embodiments disclosed herein (including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof) can improve (e.g., increase) ciliary axoneme production and/or elongation, ciliary biogenesis (e.g., ciliary pocket formation), and/or p62 expression. In yet additional embodiments, the compound embodiments disclosed herein (including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof) can inhibit fusion of autophagosomes with lysosomes, thereby increasing p62 expression and restoring HDAC6 degradation. Suitable controls include a standard value, the average values in a subject not treated with the compound, or the value in the subject prior to treatment. Suitable exemplary tests are disclosed in the examples. In some embodiments, therapeutic efficacy can be observed by fundus photography or evaluation of the ERG response. The method can include comparing test results after administration of the subject composition to test results before administration of the subject composition. As another example, therapeutic efficacy in treating a progressive cone dysfunction may be observed as a reduction in the rate of progression of cone dysfunction, as a cessation in the progression of cone dysfunction, or as an improvement in cone function, effects which may be observed by, such as electroretinography (ERG) and/or cERG; color vision tests; functional adaptive optics; and/or visual acuity tests, for example, by comparing test results after administration of the subject composition to test results before administration of the subject composition and detecting a change in cone viability and/or function. In some embodiments, the compound embodiments disclosed herein (including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof) defer photoreceptor loss, reduce photoreceptor function decrement, and/or reduce visual function loss. In another example, therapeutic efficacy in treating a vision deficiency can be exhibited as an alteration in the individual's vision, such as in the perception of red wavelengths, green wavelengths, and/or blue wavelengths. Such effects can be observed by using cERG and color vision tests, for example, by comparing test results obtained after administering a compound of the present disclosure to a subject to test results obtained before administering the compound, and detecting a change in cone and rod viability and/or function. In some embodiments, the method includes evaluation morphology and structure preservation and/or ERG. VI. Overview of Several Embodiments Disclosed herein are embodiments of a method of treating retinal degeneration in a subject, comprising administering to the subject a therapeutically effective amount of a compound thereby treating the retinal degeneration in the subject, wherein the compound is selected from a compound having a structure according to a formula selected from Formula I, II, or III or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof; 3-(dibutylamino)-1- (1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-o l hydrochloride or another pharmaceutically acceptable salt, or a prodrug, solvate, hydrate, or tautomer thereof; wherein, (i) with reference to Formula I, R 1 is heteroaliphatic; R 2 is OR 5 , or NR 6 R 7 , wherein each of R 5 , R 6 , and R 7 independently is selected from aliphatic, hydrogen, aromatic, or an organic functional group; R 3 is selected from aliphatic, aromatic, acyl, or sulfonyl; R 4 is selected from acyl, aliphatic, aromatic, or sulfonyl; and n is an integer selected from 0 to 4; (ii) with reference to Formula II, R A , is selected from halogen, heteroaliphatic, haloaliphatic, or an organic functional group; R B is aromatic; and each of R C and R D independently is selected from hydrogen, aliphatic, or heteroaliphatic; and m is an integer selected from 0 to 4; and (iii) with reference to Formula III, R’ is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or an organic functional group; each R’’ independently is selected from halogen, heteroaliphatic, or amino; each R’’’ independently is selected from halogen, heteroaliphatic, or amino; p is an integer selected from 0 to 4; q is an integer selected from 0 to 4; and r is an integer selected from 0 or 1. In some embodiments, the subject has retinitis pigmentosa, LCA, Stargardt's macular dystrophy, cone-rod dystrophy, choroideremia or age-related macular degeneration. In any or all of the above embodiments, the compound is administered orally. In any or all of the above embodiments, the compound is administered locally to the eye of the subject. In any or all of the above embodiments, the compound is administered intravitreally. In any or all of the above embodiments, the subject is human. In any or all of the above embodiments, the compound maintains thickness of a nuclear layer of photoreceptors in a retina of the eye of the subject. In any or all of the above embodiments, the compound increases expression of a photoreceptor ciliary opsin and/or a phototransduction protein in the eye of the subject. In any or all of the above embodiments, the photoreceptor ciliary opsin is rhodopsin or S-opsin, or rod cyclic GMP phosphodiesterase 6β (PDE6β). In any or all of the above embodiments, the compound increases the number of photoreceptor cells in the subject. In any or all of the above embodiments, the method further comprises evaluating the vision of the subject. In any or all of the above embodiments, the method comprises performing electroretinography on the subject. In any or all of the above embodiments, the compound has a structure according to any one of Formulas IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof In any or all of the above embodiments, the compound has a structure according to Formula I, IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, wherein: R 1 is alkoxy; R 2 is -OR 5 , or -NR 6 R 7 , wherein each of R 5 , R 6 , and R 7 independently is selected from hydrogen, alkyl, heteroaryl, or aryl; R 3 is selected from alkyl, heteroaryl, aryl, sulfonyl, or acyl; R 4 is selected from acyl, alkyl, heteroaryl, aryl, or sulfonyl; n is 0, 1, 2, 3, or 4. In any or all of the above embodiments, the compound has a structure according to Formula I, IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, and wherein R 4 is selected from or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. In any or all of the above embodiments, the compound has a structure according to Formula IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof In any or all of the above embodiments, the compound has a structure according to Formula II or IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, wherein: each R A independently is selected from halogen, -OMe, -CN, or -CF 3 ; R B is selected from aryl; aryl comprising one or more substituents selected from halogen, -CF 3 , -CN, -OH, alkyl, or alkoxy; heteroaryl; heteroaryl comprising one or more substituents selected from halogen, - CF 3 , -CN, -OH, alkyl, or alkoxy; each of R C and R D independently is selected from hydrogen, alkyl, or amino; and m is 0, 1, 2, 3, or 4. In any or all of the above embodiments, the compound has a structure according to Formula II or IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, and R B is selected from In any or all of the above embodiments, the compound is , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof In any or all of the above embodiments, the compound has a structure according to Formulas IIIA- IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof In any or all of the above embodiments, the compound has a structure according to Formula III or IIIA-IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, and wherein R’ is selected from halo, -CN; -CF 3 ; -OCF 3 ; alkyl; heteroalkyl comprising one or more nitrogen atoms, one or more oxygen atoms, one or more sulfur atoms, or a combination thereof; or aminoaryl; R’’ is selected from halogen, alkoxy, or -NR a’ R b’ , wherein each of R a’ and R b’ independently is selected from alkyl, heteroalkyl, benzyl, acyl, sulfonyl; R’’’ is selected from halogen, alkoxy, or -NR a’ R b’ , wherein each of R a’ and R b’ independently is selected from alkyl, heteroalkyl, benzyl, acyl, or sulfonyl; p and q independently is an integer selected from 0, 1, 2, 3, or 4; and r is 0 or 1. In any or all of the above embodiments, the compound has a structure according to Formula III or IIIA-IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, wherein R’ is selected from
wherein R’’ and R’’’ independently is -NR a’ R b’ , wherein one of R a’ and R b’ is H and the other is selected from
. In any or all of the above embodiments, the compound is selected from
a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. In any or all of the above embodiments, the compound is selected from
. Also disclosed herein are embodiments of a composition, comprising a therapeutically effective amount of a compound according to any or all of the above embodiments for use in treating retinal degeneration in a subject. In any or all of the above embodiments, the composition is formulated for oral administration. In any or all of the above embodiments, the composition is included in a dosage form. In any or all of the above embodiments, the composition is formulated for local administration to the eye. In any or all of the above embodiments, the composition is formulated for intravitreal administration. In any or all of the above embodiments, the composition further comprises a therapeutically acceptable excipient. Also disclosed herein are embodiments of a composition comprising a therapeutically effective amount of a compound for use in the method of any one of any or all of the above embodiments, wherein the compound is selected from 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanth ren-9-yl)propan-1- ol hydrochloride or another pharmaceutically acceptable salt, or a prodrug, solvate, hydrate, or tautomer thereof; or a compound having a structure according to a formula selected from Formula I, II, or III or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof; wherein, with reference to Formula I, R 1 is heteroaliphatic; R 2 is OR 5 , or NR 6 R 7 , wherein each of R 5 , R 6 , and R 7 independently is selected from aliphatic, hydrogen, aromatic, or an organic functional group; R 3 is selected from aliphatic, aromatic, acyl, or sulfonyl; R 4 is selected from acyl, aliphatic, aromatic, or sulfonyl; and n is an integer selected from 0 to 4; with reference to Formula II, R A , is selected from halogen, heteroaliphatic, haloaliphatic, or an organic functional group; R B is aromatic; and each of R C and R D independently is selected from hydrogen, aliphatic, or heteroaliphatic; and m is an integer selected from 0 to 4; and with reference to Formula III R’ is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or an organic functional group; each R’’ independently is selected from halogen, heteroaliphatic, or amino; each R’’’ independently is selected from halogen, heteroaliphatic, or amino; p is an integer selected from 0 to 4; q is an integer selected from 0 to 4; and r is an integer selected from 0 or 1. VII. Examples The disclosure is illustrated by the following non-limiting Examples. Example 1 The ether analogs are prepared through Williamson ether synthesis from the reaction of an alkyl halide with 100 under basic conditions (1). The acyl-functionalized analogs are synthesized from the reaction of 100 with carboxylic acids under the coupling reagents (3) or corresponding acyl chloride (2). Sulfonyl analogs are produced from the reaction of 100 with corresponding sulfonyl chloride (4). In specific examples, reserpic acid methyl ester 100 is dissolved in toluene, then R 4 I and Ag2O are added and the resulting mixture is heated in an 80 °C oil bath for 6-12 hours, after which most of the starting material 100 is converted. The product is then filtered and the filtrate is collected, concentrated, and purified using a CombiFlash® purification system. Reserpic acid methyl ester 100 and DIPEA are dissolved in DCM and the resulting mixture is cooled in a 4 °C in ice-water bath. The acyl halide reagent (obtained either from a commercial source or made according to procedures known in the art), are added (as a solution in DCM) dropwise over 5 minutes. The reaction mixture is then allowed to warm to room temperature over a period of 1-5 hours. Once the reaction is finished (as monitored by LCMS to confirm that all starting material is converted), it is filtered to remove insoluble salts and the filtrate is collected, concentrated, and purified using a CombiFlash® purification system. To a solution of a carboxylic acid, coupling reagent (DCC, EDC), DIPEA and DPAM in DCM, which are cooled into 4 °C in ice-water bath, is added reserpic acid methyl ester 100. Then, the reaction mixture is allowed to warm to room temperature over a period of 12-24 hours. Once the reaction is finished (as monitored by confirm that all starting material is converted), it is filtered to remove insoluble salts and the filtrate is collected, concentrated, and purified using a CombiFlash® purification system. Sulfonate analogs Reserpic acid methyl ester 100 and DIPEA are dissolved in DCM, and the resulting mixture is cooled into 4 °C in an ice-water bath. A sulfonyl chloride reagent (obtained either from a commercial source or made according to procedures known in the art), in a DCM solution, is added dropwise over 5 minutes. The reaction mixture is allowed to warm to room temperature over a period of 1-5 hours. Once the reaction is finished (as monitored by confirm that all starting material is converted), it is filtered to remove insoluble salts and the filtrate is collected, concentrated, and purified using a CombiFlash® purification system. Example 2 To a solution of a precursor (102, 104, or 106) dissolved with MeOH/H 2 O is added LiOH. The resulting mixture is stirred under room temperature for 20-48 hours until most of starting material is converted. The mixture is concentrated, dissolved with DCM/Water, acidified by HCl, then collected the organic phase, which is dried under Na2SO4, filtrated, concentrated, dried under high vacuum, ready for next-step to use without further purification. While the above scheme shows the method for preparing the corresponding ester products (110, 112, and 114), amides also can be prepared by replacing the alcohol reagent (R 5 OH) with an amine reagent (e.g., R 6 R 7 NH) and DIPEA and benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (or “PyBOP”). Example 3 In this example, compounds according to Formula II are prepared. In some examples, a precursor 200 is used in a Suzuki coupling with boronic acid 208, which are commercially available or can be prepared using methods known to those of ordinary skill in the art with the benefit of the present disclosure. Cs 2 CO 3 and the boronic acid 208 are added to precursor 200 in dioxane/H 2 O=10:1, which is degassed by nitrogen gas bubbling, and to which is added Pd(PPh 3 ) 4 . The reaction mixture is capped and irradiated through microwave at 80 °C for 1 hour. The resulting solution is filtered, concentrated, and purified using CombiFlash® purification system to provide product 210. To a solution of 210 in DCE is added the aldehyde reagent and NaBH(OAc) 3 . The resulting mixture is stirred for 12-24 hours and monitored by LCMS. The mixture is concentrated and purified using a CombiFlash® purification system to provide product 212. Example 4 In this example, compounds of Formula III are made. In some examples, precursor 318 can be converted to product 320, wherein R is as recited herein for Scheme 3A. The “RONa” reagent can be purchased commercially or prepared by reacting the corresponding alcohol with Na or NaOH. Then to a solution of precursor 318 in dioxane is added RONa, and the reaction vessel is capped and the reaction mixture was heated at 100-120 °C for 10-24 hours. The reaction mixture is concentrated and then purified using a CombiFlash® purification system to provide product 320. In some additional examples, compounds like amine-functionalized Scheme compound 310 (Scheme 3A) can be made using methods as illustrated in Scheme 3A. In some examples, to a solution of starting material 318 in DMF is added K 2 CO 3 , and the desired amine reagent. The reaction vessel is capped and the reaction mixture is heated at 100-120 °C for 10-24 hours. The reaction mixture is concentrated and then purified using a CombiFlash® purification system to provide a product according to Formula 310 of Scheme 3A. In some other examples, to a solution of starting material 318 in EtOH is added HCl dissolved in dioxane and the desired amine reagent. The reaction vessel is capped and the reaction mixture is heated at 100-120 °C for 10-24 hours. The reaction mixture is concentrated and then purified using a CombiFlash® purification system to provide a product according to Formula 310 of Scheme 3A. In yet additional examples, to a solution of starting material 318 is added Cs 2 CO 3 and an aryl amine coupling partner in dioxane. The reaction vessel is degassed by nitrogen gas bubbling and then Pd(OAc) 2 and Xantphos are added. Then reaction vessel is capped and irradiated through microwave at 80 °C for 1 hour. The reaction mixture is filtered, concentrated, and then purified using a CombiFlash® purification system to provide a product according to Formula 312 of Scheme 3A. Example 5 In this example, compounds according to Scheme 3B are made. In particular embodiments, compounds having a formula 316 (Scheme 3B) are made by providing a solution of acridine-3,6-diamine and DIPEA dissolved in DCM and cooling it in a 4 °C in ice-water bath. Then, the desired acyl chloride or sulfonyl chloride is added dropwise over 5 minutes. The reaction is allowed to warm to room temperature, and is further stirred for 1-3 hours. The reaction mixture is filtered to remove the insoluble salt, the filtrate is collected and concentrated and then purified using a CombiFlash® purification system to product a compound according to formula 316 from Scheme 3B. In these embodiments, compound 316 is a symmetrical amine. Asymmetric amines can be made by using different coupling partners as illustrated in the scheme below: Sulfonyl-containing compounds are made as illustrated below. In particular embodiments, a solution of acridine-3,6-diamine and DIPEA dissolved in DCM is cooled in a 4 °C in ice-water bath, and sulfonic acid chloride is added dropwise over 5 minutes. The reaction is allowed to warm to room temperature, and is further stirred for 1-3 hours. The reaction mixture is filtered to remove the insoluble salt, the filtrate is collected and concentrated and then purified using a CombiFlash® purification system to provide the sulfonyl-containing product. In yet additional examples, other amine compounds can be made by mixing a solution of acridine- 3,6-diamine and NaHCO 3 dissolved in THF/water with Boc 2 O. The resulting mixture is stirred overnight and extraction is conducted to provide a crude Boc-protected acridine-3,6-diamine. Deprotonation is performed using NaH and the desired R a’ or R b’ group is added. The Boc protecting group is then removed using TFA. Example 6 Neural retina in organoids derived from induced pluripotent stem cells (iPSCs) of CEP290-LCA subjects display disease-associated defects - Leber congenital amaurosis (LCA) is an early onset inherited blinding disease that is caused by defects in over 20 different genes. In addition to photoreceptor development and/or function, genetic defects associated with LCA can impact other tissues and present a syndromic clinical phenotype. CEP290 is a cilia-centrosomal protein that is a critical component of transition zone and likely controls trafficking of ciliary proteins. Defects in CEP290 can result in multiple syndromic phenotypes with LCA believed to be towards the milder spectrum. Human pluripotent stem cell (PSC), including embryonic stem cells (ESC) and iPSCs, can be differentiated into retinal organoids with laminated neural retina and photoreceptors with rudimentary outer segment-like structure. To investigate whether the human organoid culture system can recapitulate disease- associated phenotypes observed in CEP290-LCA subjects, a family comprised of a phenotypically normal mother (control) and her two LCA offspring (LCA1 and LCA2) was recruited. Control and subject iPSCs were reprogrammed from fibroblasts and differentiated into retinal organoids. Aberrant phenotypes were identified in subject retinal organoids in comparison to the control. In control organoids, the rod photoreceptor opsin – rhodopsin – was evident at differentiation day (D) 120, followed by its polarization to the apical side of neural retina at D150, and transport to the outer segment region by D200 (FIG.2A). However, in LCA1 organoids, although rhodopsin could be observed throughout development, it could not be delivered to the outer segments and remained mis-localized in the cell body. LCA2 organoids displayed even more severe phenotypes, as shown by the lack of robust rhodopsin expression. Although cone opsin OPN1SW and OPN1MW was less robust compared to the control neural retina, no significant morphological difference could be observed in cone photoreceptors between control and subject organoids. Immunostaining of connecting cilia and ciliary axoneme marker ARL13B revealed that aberrant photoreceptor development in subject organoids could be caused by ciliary defects in photoreceptors (FIG. 2B). ARL13B staining was concentrated in the connecting cilia of control photoreceptors and elongated along the differentiation process as the outer segment developed. In contrast, consistently in both subject organoids, the photoreceptors demonstrated aberrant development of the connecting cilia and lacked outer segment biogenesis. To determine gene/signaling pathway signatures in CEP290-LCA subject organoids for understanding disease mechanisms and evaluating effective treatments, control and subject organoid samples were harvested at D67, D90, D120 and D150, and a transcriptome analysis was performed. Principle component analysis showed that control and subject organoid samples roughly separated into two groups across differentiation, suggesting discrepancies in gene profiles between control and subject samples (FIG.2C). Differential expression analysis revealed the largest discrepancies between control and subject samples occurred at D90 and D120, with 2026 and 1911 differentially expressed (DE) genes, respectively, compared to 162 at D67 and 190 at D150 (FIG.2D). To isolate the DE genes caused by mutations but not development, an age-matched pairwise comparison was performed between control and subject transcriptomes and the DE genes that were due to developmental stage were removed (FIG.2E). The 779 unique genes in this analysis belonged to signaling pathways associated with metabolism of proteins, vesicle-mediated transport, membrane trafficking, translation, the citric acid cycle and protein processing in endoplasmic reticulum (FIG.2F). Notably, expression of phototransduction genes, which are important for photoreceptor function, were mostly down-regulated in subject organoids (FIG.2G). Example 7 High-throughput phenotypic screening in mouse retinal organoids identified compound embodiments that maintain rod photoreceptor survival - A representative method for identifying compound embodiments of the present disclosure as compounds useful for treating retinal degeneration, particularly for treating retinal ciliopathies (including those associated with CEP290 defects), is shown by FIG.3. As pathogenic mechanisms of CEP290-associated diseases are largely unclear, it was decided to perform untargeted high-throughput screening (HTS) to identify compound embodiments to maintain photoreceptor survival. Due to technical challenges, human iPSC differentiation into retinal organoids could hardly meet the large-scale demand of cells in HTS. As cilia biogenesis is largely conserved between mice and human (Soares et al., 2 Cells, 8, 2019), a multiplexed HTS platform was set up using retinal organoids derived from iPSCs of Nrl-GFP rd16 mouse (a model of CEP290-LCA, (Chang et al., Hum Mol Genet, 15, 1847-57, 2006)). These organoids could be generated from iPSCs efficiently with comparatively much shorter differentiation time (Chen et al., Mol Vis, 22, 1077-1094, 2016). The GFP tag under the control of the promoter of Nrl, which is the first postmitotic marker of rod photoreceptors (Akimoto et al., Proc Natl Acad Sci USA, 103, 3890-5, 2006), provided a tool to monitor rod cell biogenesis in organoid cultures. Based on the >30% lower GFP+ cells and >50% lower viability in Nrl-GFP rd16 iPSC-derived retinal organoids, a compound discovery pipeline was developed to maintain rod photoreceptor viability through screens to identify compound embodiments to increase the fluorescence intensity of GFP and nuclei stain 4′,6- diamidino-2-phenylindole (DAPI), followed by validation of the hits in mouse retinal organoids. The hits were further confirmed by transcriptome analysis, subject iPSC-derived retinal organoids, and rd16 mouse retina in vivo (FIG.3). In the primary screens, rd16 retinal organoids at D26, when photoreceptor cilia started to grow and abnormal phenotypes could be observed, were dissociated into single cells (GFP+ cells representing rod photoreceptors) and plated at a density of 4,000 cells/well of 1,536-well plates. D30 retinal organoids were also plated as positive control. After 24 hours, approximately 6000 small molecules from libraries of Sigma LOPAC, FDA-approved drugs, and agonists and antagonists of major cellular signaling pathways were applied to the cells at 7 different concentrations, with DMSO (solvent for small molecules) as control. After 48-hour incubation, the treated cells were fixed and stained with DAPI. By gating with the untreated group, approximately 100 compounds seemed to show positive effects on GFP and DAPI signal intensity. To remove false positive hits due to the autofluorescence of compounds, these initial hits from primary screens were applied to dissociated D26 organoids differentiated from parental PSC-derived organoids, which do not harbor GFP marker. Compounds with high autofluorescence signal were then eliminated from subsequent experiments. After normalization with DMSO control, 14 compound embodiments were selected based on their potency that was calculated as the concentration of half-maximal activity derived from the Hill equation model. Example 8 Rhodopsin and S-opsin expression were increased in rd16 retinal organoids treated with compound embodiments - The 14 compound embodiments were then tested with intact rd16 retinal organoid cultures at AC50 and half of AC50 to evaluate their toxicity and effect. Small molecules leading to dissociation of retinal organoids or photoreceptor death at 0.5x AC 50 would be removed from subsequent validation. The compounds were applied directly to the cultures at D22 and removed at D25. Treated organoids were harvested 72 hours after removal of compounds at D28 (FIG.4A). Five compound embodiments (NCGC0091250, Reserpine; NCGC00253604, Rescimetol; NCGC00263128, CHEMBL39740; NCGC00015874, Quinacrine dihydrochloride dihydrate; NCGC00166245, Proflavine hemisulfate) demonstrated higher immunostaining of markers for rod and/cone photoreceptors in rd16 organoid cultures. As shown in FIG.4B, immunostaining of rhodopsin in untreated rd16 photoreceptors is very faint, with loss of polarity at the apical side of neural retina. Treatment with these compound embodiments improved expression and polarity of rhodopsin, with variable potency. Notably, although cone photoreceptor biogenesis was compromised even in WT organoids at D28, some compound embodiments, NCGC0091250 for example, were able to increase the expression and polarization of S-opsin in cone photoreceptors, suggesting a favorable effect on S-cones as well. To account for high variability of mouse retinal organoids, the fluorescence intensity of rhodopsin and S-opsin staining in all untreated and treated neural retina (FIG. 4C) was quantified using an imaging algorithm that captured most pixels and avoided background in immunostaining. The improvement was confirmed with selected compound embodiments on rod and/or cone photoreceptors in rd16 retinal organoids. NCGC00253604 is a derivative of NCGC0091250, but it is not as potent as NCGC0091250 showing only borderline improvement of rhodopsin staining in mouse retinal organoids. Example 9 Subject iPSC-derived retinal organoids showed improvement in photoreceptor biogenesis after treatment with compound embodiments - To further validate the five compound embodiments, LCA subject iPSCs were differentiated into retinal organoids and treated with the selected small molecules. Comparative transcriptome analysis of gene profiles of control and subject retinal organoids indicated that the most dramatic divergence was observed at D120 (FIG.2D). Therefore, drug treatments were applied at D110 and D135, each of which lasted for 3 days, and retinal organoids were harvested at D125 and D150 for evaluation of photoreceptor and cilia biogenesis by immunostaining (FIG.5A). Due to the different sensitivity of small molecules and the reversed configuration of neural retina between mouse and human retinal organoids, 5-40 µM of each compound was re-evaluated in subject organoids. One compound embodiment, NCGC00166245, demonstrated toxicity in organoids of one of the subjects within this range and was removed from further validation experiments. The remaining 4 were applied to subject organoid cultures. D150 subject organoids had barely detectable rhodopsin and limited development of ciliary axoneme, which were improved by treatment of different small molecules (FIG.5B). Although cone photoreceptors were not dramatically impacted in subject organoids, the improvement of cone cells was noted in subject organoids with two small molecule treatments (NCGC0091250, NCGC0015874), which is consistent with their effects on mouse organoids (FIG.5C). Treatment of NCGC00253604, a derivative of NCGC009125, demonstrated a more potent effects on human rod photoreceptors compared to mouse ones. Example 10 Intravitreal injection of compound embodiments into rd16 mouse maintained the thickness of the outer nuclear layer of photoreceptors - To verify the compound embodiments in vivo, intravitreal injection was preformed, to deliver the compounds into Nrl-GFP rd16 mouse retina and assess the survival of photoreceptors in the outer nuclear layer (ONL). As differences between wildtype and rd16 mouse retina appear as early as postnatal day (P) 6, the compound was delivered intravitreally at P4, with one eye receiving DMSO (control) and the other eye candidate compounds. The eyes were harvested at P21 (FIG. 6A). To systematically assess technical issues including injection techniques, compound concentration and toxicity, the experiment was started with one compound NCGC0091250, which revealed the most significant effect in mouse and human organoids. In 2 out of the 3 injected animals, injection of 40 µ M NCGC0091250 maintained the thickness of ONL at P21, as shown by GFP (rod cells) and DAPI (FIG.6B), compared to the control eye without treatment. Photoreceptor ciliary proteins, including rod-specific proteins rhodopsin (RHO) and cyclic GMP phosphodiesterase ß (PDE6ß), were transported to the outer segment region. Consistently, treated retina had more ciliary proteins located at the longer outer segments compared to the untreated ones. In all three injected mice, no obvious toxicity was observed. Example 11 Evaluation of the drug effect on subject retinal organoids - The timeline for the drug treatment on CEP290-LCA (IVS26+1655A>G p.C998X; c.5668G>T p.G1890X) is show in FIG.7A. Subject induced pluripotent stem cells (iPSC)-derived retinal organoids were used and two treatment modules were evaluated: (1) intermittent high dose (20 ^M and 30 ^M); and (2) continuous low dose (10 ^M). The treatments started 3 days before abnormal phenotypes in subject organoids could be observed (D117) and the organoids were harvested at D150 for analyses. The drug vehicle DMSO was added as control with a concentration (v/v) less than 1%. FIGS.7B and 7C show the Western blot analyses and quantification rhodopsin level in subject organoids, respectively. The data are presented as mean ± standard deviation from 2 batches of experiments, each of which had at least 2 retinal organoids. Beta-actin (ACTB) were used as a loading control. As determined from the data, retinal organoids from both subjects harbored a lower expression of rhodopsin compared to those from the familial control (labeled as “C” in FIGS.7B and 7C), suggesting defects in rod photoreceptors. Treatments of different concentrations of reserpine (labeled as “R” in FIGS. 7A-7C) were able to improve rhodopsin staining. In this example, 30 ^M reserpine exhibited a positive effect in subject 1, whereas 10 ^M was sufficient for subject 2, possibly indicating variations in subjects or cell lines. The images shown by FIGS.7D and 7E confirmed the results of the Western blot that reserpine showed improved both photoreceptors and ciliary axoneme in subject organoids. Example 12 Evaluation of misregulation of autophagy in subject organoids - As the common pathway of all the positive hits in the rd16 organoids mouse was autophagy inhibition, the autophagy level in subject retinal organoids was assessed. Autophagy is a cellular homeostatic mechanism whose initiation could be induced by stress, leading to phosphorylation of ULK1 (see FIG.8A). Together with other autophagy components ATG101 and ATG13, p-ULK1 triggers the formation of phagophore, which is an extension of the endoplasmic reticulum membrane. A key autophagy adaptor p62 binds to ubiquitinated cellular components and delivers them to phagophores to form a sealed vesicles termed autophagosome. LC3-II, a standard marker for autophagosomes, is generated by conjugation of cytosolic LC3-I to phosphatidylethanolamine (PE) on the surface of nascent autophagosomes LC3-II. Cellular components in the autophagosome are degraded by fusion with lysosomes. To evaluate the overall autophagic status in subject organoids, several components in the process, including p-ULK1, ULK1, p62 and LC3, were evaluated. FIGS.8B summarizes the timeline used for the evaluations in this example. As cilium biogenesis and photoreceptor maturation start at around D90, control and subject organoids were harvested at D60 and D120 to evaluate the impact of ciliary defects on cellular autophagy. FIGS.8C and 8D-8G show Western blot analyses and autophagy component quantification in subject organoids, respectively (the data are presented as mean ± standard deviation from 2 batches of experiments, each of which had at least 3 retinal organoids); beta-actin (ACTB) were used as a loading control. At D60, no significant difference was found in the tested autophagy components between control and subject organoids; however, an augmented autophagy initiation could be observed in subject organoids, as shown by upregulation of p-ULK1. A significantly down-regulation of p62 and up-regulation of LC3-II consistently indicated misregulation of the autophagic flux in subject organoids compared to the control. Example 13 Drug repurposing of autophagy inhibitors - To confirm the effect of autophagy inhibition on rescuing subject photoreceptors and to identify key autophagic molecule(s) involved in this process, various FDA- approved autophagy inhibitor drugs were applied on organoid cultures at their reported AC 50 and 2x AC 50 (summarized by FIG.9A). MRT68921 and Lys05 inhibit phosphorylation of ULK1. Chloroquine (Q), hydroxychloroquine (HQ) and ROC-325 increase the pH of lysosomes to prevent their fusion with autophagosomes. MRT68921 and Lys05 exhibited high toxicity even at 0.5x AC50 (data not shown) and thus were omitted in subsequent analyses. FIG.9B shows the results from immunostaining of rod (rhodopsin, green), S-cone (S-opsin, red) and L/M-cone (L/M-opsin, magenta) photoreceptors. The immunostaining analyses revealed a positive effect of all autophagy inhibitors on subject photoreceptors, although with various efficacies, suggesting that autophagy inhibition plays a role in maintenance/improvement of photoreceptors in retinal degenerative diseases. Example 14 p62 mediation - In this example, the increase of p62 by reserpine in treated subject organoids was evaluated. FIGS.10A and 10B show Western blot analyses and p62 and LC3-II quantification, respectively. As can be seen in FIG.10B, LC3-II level decreased in one subject but not the other one. Notably, a more significant change of p62 was observed in the subject more responsive to reserpine treatment. FIGS.10C show the results from immunostaining of p62 and acetylated tubulin (DM1T) in treated subject organoids, which were performed to confirm an increase of p62 in photoreceptors in subject organoids treated by reserpine and hydroxychloroquine (HQ). DM1T staining also indicated more well developed ciliary axoneme in treated subject photoreceptors. FIGS.10D and 10E show Western blot analyses and quantification of p62 interaction partner and cilium disassembly key driver, HDAC6, and other ciliary regulatory proteins, including IFT88 (intraflagellar transport), BBS6 and CEP164 (distal appendage component for initiation of ciliogenesis) in treated organoids. Down-regulation of HDAC6 and up- regulation of CEP164 were observed in subject organoids treated with reserpine. As HDAC6 is a major driver for cilium biogenesis and CEP164 is located in distal appendage of docking of preciliary vesicles for initiation of ciliogenesis, transmission electron microscopy (TEM) was performed to uncover more details of photoreceptors in untreated and treated subject organoids. Defects in docking of preciliary vesicles and formation of ciliary membrane have been reported to be early phenotypes in CEP290-LCA subject retinal organoids, and such defects could be alleviated by treatment of reserpine (see FIG.10F, upper panel). TEM analyses also revealed longer ciliary axoneme in treated photoreceptors (see FIG.10F, lower panel). Notably, a well-organized disc-like structure, which is rare in organoid culture, could be observed in subject organoids (see FIG.10G), suggesting a favorable effect of reserpine on the development of outer segment (primary cilium of photoreceptors). Example 15 Improved photoreceptor morphology after short-term treatment of CEP290-LCA subject induced pluripotent stem cell (iPSC)-derived retinal organoids - To evaluate the effect of reserpine on subject organoids caused by a different mutation, short-term treatment of reserpine on CEP290-LCA subject organoids caused by homozygous IVS26+1655A>G p.C998X, which is the most common mutations of CEP290-LCA, was performed. FIG.11A provides a schematic diagram showing the small molecule treatment paradigm for CEP290-LCA retinal organoids used for this example. FIG.11B shows the images obtained from immunostaining of rod cells (green), S-cones (red) and L/M-cones (magenta). The images confirm that CEP290-LCA retinal organoids homozygous for IVS26+1655A>G p.C998X displayed defects in photoreceptor development and treatment of reserpine was able to improve rod photoreceptors in cultures. In view of the many possible embodiments to which the principles of the present disclosure may be applied, it should be recognized that the illustrated embodiments are only preferred examples and should not be taken as limiting the scope of the disclosure. Rather, the scope is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.