# US 10,369,141 B2 · Methods of improving cell-based therapy

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- Number: US 10,369,141 B2
- Document ID: US10369141B2
- Status: Granted
- Kind: B2
- Application number: 15/915,637
- Filed: 2018-03-08
- Published: 2018-07-19
- Granted: 2019-08-06
- Earliest claimed: 2014-06-16
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Nipavan Chiamvimonvat; Bruce D. Hammock
- Web page: https://patentgrep.com/patent/US10369141B2

## CPC

- A61K 31/4468: having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
- A61K 9/7023: {Transdermal patches and similar drug-containing composite devices, e.g. cataplasms (galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006)}
- A61K 31/17: having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64)
- A61K 31/195: having an amino group
- A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205)
- A61K 31/22: of acyclic acids, e.g. pravastatin
- A61K 31/336: having three-membered rings, e.g. oxirane, fumagillin
- A61K 31/415: 1,2-Diazoles
- A61K 31/4465: only substituted in position 4
- A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
- A61K 35/34: Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes (vascular smooth muscle A61K35/44)
- A61K 35/545: Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
- A61L 31/005: {Ingredients of undetermined constitution or reaction products thereof}
- A61L 31/16: Biologically active materials, e.g. therapeutic substances {(A61L31/047 takes precedence)}
- A61L 2300/432: Inhibitors, antagonists (A61L2300/402 - A61L2300/43 take precedence)
- A61L 2300/64: Animal cells
- A61L 2430/20: for reconstruction of the heart, e.g. heart valves
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)

## Abstract

Provided are methods for improving cell-based therapies by co-administration with an agent that increases the production and or levels of epoxygenated fatty acids, as well as kits, stents and patches for co-administering stem cells with an agent that increases the production and/or levels of epoxygenated fatty acids.

## Claims

### Claim 1

A method of increasing the survival, engraftment and/or integration of transplanted induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) into cardiac tissue of a subject in need thereof, comprising co-administering to the subject the hiPSC-CMs with an agent that increases the production and/or level of epoxygenated fatty acids, wherein the co-administration results in an increase in the survival, engraftment and/or integration of the transplanted hiPSC-CMs relative to administration of the hiPSC-CMs alone.

### Claim 2

A method of reversing, mitigating and/or improving one or more symptoms associated with cardiomyopathy or cardiac arrhythmia in an subject in need thereof, said method comprising co-administering to said subject a population of induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and an agent that increases the production and/or level of epoxygenated fatty acids.

### Claim 3 (depends on 1)

The method of claim 1, wherein the subject has cardiomyopathy, and wherein the cardiomyopathy is one or more of hypertrophic cardiomyopathy, hypertensive cardiomyopathy, diabetic cardiomyopathy and dilated cardiomyopathy.

### Claim 4 (depends on 2)

The method of claim 2, wherein said cardiomyopathy is due to or secondary to one or more of valvular heart disease, myocardial infarction, and familial hypertrophic cardiomyopathy, and wherein said valvular heart disease is secondary to rheumatic fever, myxomatous degeneration of the valve, or papillary muscle dysfunction.

### Claim 5 (depends on 2)

The method of claim 2, wherein the cardiomyopathy is dilated cardiomyopathy, and wherein said dilated cardiomyopathy is one or more of alcohol-induced cardiomyopathy, viral-induced cardiomyopathy, idiopathic cardiomyopathy, familial dilated cardiomyopathy and dilated cardiomyopathy caused by administration of an anti-cancer drug or exposure to a toxic agent.

### Claim 6 (depends on 2)

The method of claim 2, wherein the administration of said hiPSC-CMs and said agent or agents inhibits cardiac arrhythmia, wherein the cardiac arrhythmia is one or more of atrial fibrillation, atrial flutter, ventricular fibrillation and ventricular tachycardia.

### Claim 7 (depends on 1)

The method of claim 1, wherein the agent comprises one or more epoxygenated fatty acids.

### Claim 8 (depends on 1)

The method of claim 1, wherein the epoxygenated fatty acids are selected from the group consisting of cis-epoxyeicosatrienoic acids (“EETs”), epoxides of linoleic acid, epoxides of eicosapentaenoic acid (“EPA”), epoxides of docosahexaenoic acid (“DHA”), epoxides of the arachidonic acid (“AA”), epoxides of cis-7,10,13,16,19-docosapentaenoic acid, and mixtures thereof.

### Claim 9 (depends on 1)

A method of claim 1, wherein the agent is an inhibitor of soluble epoxide hydrolase (“sEH”).

### Claim 10 (depends on 9)

The method of claim 9, wherein the inhibitor of sEH comprises a primary pharmacophore selected from the group consisting of a urea, a carbamate, and an amide.

### Claim 11 (depends on 9)

The method of claim 9, wherein the inhibitor of sEH comprises a phenyl ether or piperidine moiety attached to the pharmacophore.

### Claim 12 (depends on 9)

The method of claim 9, wherein the inhibitor of sEH has an IC50 of less than about 100 μM.

### Claim 13 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 14 (depends on 1)

The method of claim 1, wherein the hiPSC-CMs are syngeneic, allogeneic or xenogeneic to the subject.

### Claim 15 (depends on 1)

The method of claim 1, wherein the hiPSC-CMs are administered intravenously, intra-arterially or intralesionally.

### Claim 16 (depends on 1)

The method of claim 1, wherein the hiPSC-CMs and the agent that increases the production and/or level of epoxygenated fatty acids are administered by different routes of administration.

### Claim 17 (depends on 9)

The method of claim 9, wherein the hiPSC-CMs and the inhibitor of sEH are concurrently co-administered.

### Claim 18 (depends on 9)

The method of claim 9, wherein the hiPSC-CMs and the inhibitor of sEH are sequentially co-administered.

### Claim 19 (depends on 1)

The method of claim 1, wherein the hiPSC-CMs are syngeneic to the subject.

### Claim 20 (depends on 1)

The method of claim 1, wherein the hiPSC-CMs are allogeneic to the subject.

### Claim 21 (depends on 1)

The method of claim 1, wherein the hiPSC-CMs are xenogeneic to the subject.