THE SPINAL CORD

[0001] This application claims priority to US provisional application no. 62/843,663, filed May 6, 2019, the disclosure of which is incorporated herein by reference.

Field of the Invention

[0002] The field of the invention is methods, systems, kits, and devices related to improving delivery of therapeutics to patients.

Background

[0003] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0004] When developing possible therapies for neurological conditions, diseases, or disorders, a key obstacle is how the therapy will be delivered or administered to the therapeutic region of interest in the brain. While surgical administration to the brain is possible, in many cases it is unfavorable as it requires access through sensitive intermediate brain tissue and otherwise poses risk of contaminating brain matter, for example with prions. Methods of indirect administration are also known, such as administering therapeutic agents to the blood stream or applying energy pulses to portions of the brain or central nervous system. For example, Kapural et al, Novel 10kHz High-Frequency Therapy (HF10 Therapy), Anesthesiology 2015 (“Kapural”) teaches using electrical pulses via spinal epidural electrodes at vertebral levels to reduce sensation of chronic pain, including pulses of short duration (e.g., 30ps), high frequency (e.g., 10kHz), and low amplitude (e.g., lmA-5mA). Likewise, WO2014/164414 to Rezai teaches using electrodes to stimulate the spinal sections and spinal nervous tissue of patients, including in some cases delivering drugs or stem cells to those spinal sections, in order to treat post-traumatic stress related disorders. However, such teachings affect spinal tissue primarily and do not relate to applying therapeutics to brain tissue. Further, while West et al, Association of Epidural Stimulation with Cardiovascular Function, JAMA Neurology 2018 teaches stimulation of lumbosacral spinal cord can be used in patients with motor-complete cervical spinal cord injury to increase systolic blood pressure, middle cerebral artery blood velocity, raw steady state blood pressure, and posterior cerebral artery velocity. However, there appears to be a failure in the art to appreciate the synergistic benefits of applying spinal cord stimulation in concert with intravenous administration of brain tissue targeted therapeutics.

[0005] All publications identified herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

[0006] Thus, there remains a need for systems, methods, and devices for synergistically improving treatment outcome through intrathecal administration of therapeutics in concert with spinal cord stimulation.

Summary of The Invention

[0007] The inventive subject matter provides apparatus, systems, and methods for improving a treatment outcome from administering a therapeutic agent to a patient. A stimulation is applied to a portion of the patient’s spine, for example at one or more of the vertebrae (e.g., cervical, thoracic, lumbar, sacral, coccygeal, cauda equina, or various portions or combinations thereof), at one or more of the spinal cord segments (e.g., cervical, cervical enlargement, thoracic, lumbar, lumbosacral enlargement, sacral, coccygeal,, conus medullaris, or various portions or

combinations thereof), at one or more of the spinal nerve roots (e.g., cervical, thoracic, lumbar, sacral, coccygeal, or various portions or combinations thereof), or various portions or

combinations thereof. Preferably, the stimulation is applied at least in or around the epidural space of the patient’s spine. In preferred embodiments, application of the stimulation to the portion or portions of the patient’s spine increases a flow of blood in the patient’s spinal canal.

[0008] The inventive subject matter also contemplates devices, systems, and methods for administering a therapeutic agent to a patient. A stimulation is applied to a portion of the patient’s spinal cord, and the therapeutic agent is administered to the patient after the step of applying the stimulation. The therapeutic agent is preferably at least one of an exosome or a stem cell, and in preferred embodiments is administered intrathecally. The therapeutic agent treats a neurological condition, for example a neurodegenerative condition or a condition related to neurotrauma. Applying the stimulation preferably increases a flow of blood in the patient’s spine, for example in the spinal canal.

[0009] Uses of the inventive subject matter to treat a neurodegenerative disease or to administer an exosome or a stem cell to a patient are also contemplated.

Brief Description of the Drawings

[0010] Figure 1 depicts a method of the inventive subject matter.

Detailed Description

[0011] The inventive subject matter provides apparatus, systems, and methods for improving a treatment outcome from administering a therapeutic agent to a patient. A stimulation is applied to a portion of the patient’s spine, for example at one or more of the vertebrae (e.g., cervical, thoracic, lumbar, sacral, coccygeal, cauda equina, or various portions or combinations thereof), at one or more of the spinal cord segments (e.g., cervical, cervical enlargement, thoracic, lumbar, lumbosacral enlargement, sacral, coccygeal,, conus medullaris, or various portions or

combinations thereof), at one or more of the spinal nerve roots (e.g., cervical, thoracic, lumbar, sacral, coccygeal, or various portions or combinations thereof), or various portions or

combinations thereof. Preferably, the stimulation is applied at least in or around the epidural space of the patient’s spine. In preferred embodiments, application of the stimulation to the portion or portions of the patient’s spine increases a flow of blood in the patient’s spinal canal, preferably resulting in increased uptake of a therapeutic agent in that region.

[0012] The therapeutic agent is administered to the patient preferably after the step of applying the stimulation, but administering the therapeutic agent first or concurrently are also

contemplated, alternatively or in combination. The therapeutic agent is generally at least one of an exosome or a stem cell, though therapeutic pharmaceuticals, therapeutic molecules, or therapeutic biologies are further contemplated. Typically, the therapeutic agent is selected to treat a neurological condition, such as a neurodegenerative disease or a condition related to neurotrauma. In some embodiments, the therapeutic agent is administered intravenously, preferably intrathecally and proximal to one or more of the points of stimulation. [0013] .The stimulation is typically at least one of electrical (e.g., AC, DC, ImA, 10 mA, IOOmA, 1mA, 10mA, 100mA, 1A, IV, 10V, 100V, 500V), thermal (e.g., heat, cold), tactile (e.g., pressure, vibration), electromagnetic (e.g., applied magnetic field (e.g., MRI, fMRI), radio waves, microwaves, ionizing radiation), acoustic (e.g., infrasound, audible, ultrasound), or photonic (e.g., laser, ultraviolet, infrared, visible light), though combinations of such sources of stimulation are also contemplated. Likewise, the stimulation can be applied in pulses, for example no more than 0.1Hz, lHz, 2Hz, 5Hz, 10Hz, 100Hz, 1MHz, 1 GHz, or no more than ITHz, or durations of lps 10ps, lOOps, 1ms, 10ms, 100ms, Is, 10s, lmin, lOmin, or 30min. For preferred embodiments employing pulsed stimulation, the frequency is associated with the patient’s heart beat frequency (HB = heart beat per minute), for example 0.1HB, 0.5HB, 1HB, 2HB, 5HB, 10HB, 100HB, 1MHB, 1 GHB, or no more than 1THB. The stimulation can also be applied in a continuous fashion (e.g., heat compress at 110°F, 115°F, 120°F, 125°F, 130°F, 135°F, 140°F, etc), and can include a plurality of stimulations applied in continuous fashion (e.g., heat compress at 120°F with infrared light, etc), pulsed fashion (e.g., vibration at 100Hz with electrical pulse at lHz, etc), or combinations thereof (e.g., heat compress at 120°F for lOmin with electrical pulse at lHz for 5s, etc).

[0014] For example, in some embodiments a second stimulation is applied to a portion of the patient’s spine at least partially continuous with the first stimulation. The second stimulation is typically applied to a second portion of the spine different than the first stimulation, though at least one of the first or second stimulations is preferably directed at the epidural space of the patient’s spine. For example, in some embodiments the first stimulation is applied to the patient’s skin, while the second stimulation is applied subcutaneously. The second stimulation is generally different than the first stimulation, and is applied at a different frequency or duration.

It is contemplated that the first and second stimulations are each selected from the group of electrical, thermal, tactile, magnetic, acoustic, or photonic, and either directly (e.g., in direct contact or communication) or indirectly (e.g., stimulate the patient’s skin, neighboring tissue, or pass through tissue, etc.) affect the targeted portions of the spine. The therapeutic agent is typically administered after the first stimulation, and in some embodiments at least partially concurrent with the second stimulation. [0015] The treatment outcome is associated with the patient’s central nervous system, for example a neurological condition of the patient, preferably a neurodegenerative disease or a neurotrauma. Surprisingly, methods of the inventive subject matter including stimulation of the patient’s spine in conjunction with administering therapeutic agents to the patient improves the patient’s neurological condition by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 50%, 100%, or more than 150% compared to administering the stimulation or therapeutic agent to the patient in isolation. Moreover, the effect of stimulating the patient’s spine in combination with administering a therapeutic agent to the patient has a synergistic improvement in therapy outcome compared to the sum of the outcome achieved by either spinal stimulation or administration of therapeutic agent in isolation. For example, where spinal stimulation achieves a 10% improvement in the patient’s neurological condition, and administration of therapeutic agent achieves a 20% improvement in the patient’s neurological condition, the methods of the inventive subject matter of combining spinal stimulation with administration of therapeutic agents (e.g., exosome, stem cell, etc) surprisingly improves the patient’s neurological condition by more than 30%, for example 40%, 50%, 60%, 70%, 80%, 90%, or more than 100% improvement.

[0016] It should be appreciated that while the inventive subject matter applies stimulation to portions of the patient’s spine or neighboring tissue, the primary therapeutic effect of the inventive subject matter is to improve delivery of a therapeutic agent to the patient’s spine or nervous tissue. Indeed, stimulating the patient’s spine and administering a therapeutic agent to the patient in a concerted manner causes a synergistic improvement in the treatment of a neurological condition or trauma, and otherwise synergistically improves patient outcome.

[0017] The inventive subject matter also contemplates devices, systems, and methods for administering a therapeutic agent to a patient. A stimulation is applied to a portion of the patient’s spinal cord, and the therapeutic agent is administered to the patient after the step of applying the stimulation. The therapeutic agent is preferably at least one of an exosome or a stem cell, and in preferred embodiments is administered intrathecally. The therapeutic agent treats a neurological condition, for example a neurodegenerative condition or a condition related to neurotrauma. Applying the stimulation preferably increases a flow of blood in the patient’s spine, for example in the spinal canal. [0018] Uses of the inventive subject matter to treat a neurodegenerative disease or to administer an exosome or a stem cell to a patient are also contemplated.

[0019] Methods, systems, and devices are further contemplated for administering a therapeutic agent to a patient, including stimulating an epidural space of the patient’s spine to increase blood flow in the patient’s spinal canal and intrathecally administering the therapeutic agent to the patient, either simultaneously or in sequence, with the therapeutic agent an exosome, a stem cell, a plurality of different exosomes, a plurality of different stem cells, or some combination thereof. In preferred embodiments, the therapeutic agent is administered after, and temporally proximal, to the step of stimulating the epidural space, for example within 0.1s, Is, 2s, 3s, 4s, 5s, 10s, or 30s of stimulating the epidural space, and in some embodiments at least partially overlaps with stimulation of the epidural space.

[0020] Figure 1 depicts method 100 of the inventive subject matter, including required steps 110, 120, and 130. Optional steps 112, 114, 116, and 118 can be performed with step 110, optional steps 122, 124, and 126 can be performed with step 120, and optional step 132 can be performed with step 130, or combinations thereof.

[0021] The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art, necessary, or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0022] As used in the description herein and throughout the claims that follow, the meaning of “a,”“an,” and“the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of“in” includes“in” and“on” unless the context clearly dictates otherwise.

[0023] As used herein, and unless the context dictates otherwise, the term "coupled to" is intended to include both direct coupling (in which two elements that are coupled to each other contact each other) and indirect coupling (in which at least one additional element is located between the two elements). Therefore, the terms "coupled to" and "coupled with" are used synonymously. [0024] Unless the context dictates the contrary, all ranges set forth herein should be interpreted as being inclusive of their endpoints, and open-ended ranges should be interpreted to include commercially practical values. Similarly, all lists of values should be considered as inclusive of intermediate values unless the context indicates the contrary.

[0025] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g.“such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0026] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the

specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0027] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

[0028] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the scope of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and“comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification claims refers to at least one of something selected from the group consisting of A, B, C .... and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.