# US 2021/0275595 A1 · Naïve human embryonic vascular progenitor cells and methods of treatment

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- Number: US 2021/0275595 A1
- Document ID: US20210275595A1
- Status: Published application
- Kind: A1
- Application number: 17/180,696
- Filed: 2021-02-19
- Published: 2021-09-09
- Earliest claimed: 2020-02-20
- Assignees: The Johns Hopkins University
- Applicants: The Johns Hopkins University
- Inventors: Elias Zambidis; Tea Soon Park
- Web page: https://patentgrep.com/patent/US20210275595A1

## CPC

- A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
- A61K 35/545: Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 27/02: Ophthalmic agents
- C12N 5/0662: {Stem cells}
- C12N 5/0696: {Artificially induced pluripotent stem cells, e.g. iPS}
- C12N 2500/25: Insulin-transferrin; Insulin-transferrin-selenium
- C12N 2500/38: Vitamins
- C12N 2501/115: Basic fibroblast growth factor (bFGF, FGF-2)
- C12N 2501/15: Transforming growth factor beta (TGF-β)
- C12N 2501/235: Leukemia inhibitory factor [LIF]
- C12N 2501/724: Glycosyltransferases (EC 2.4.)
- C12N 2501/727: Kinases (EC 2.7.)
- C12N 2506/45: from artificially induced pluripotent stem cells
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Compositions are provided compositions comprising tankyrase/PARP (poly-ADP-ribose polymerase, also known as poly-ADP-ribosyltransferase) inhibitor-regulated naïve human induced pluripotent stem cells (N-hiPSCs) and their use in the treatment of vascular disorders.

## Claims

### Claim 1

A method of treating an ischemic retina of a subject in need thereof, comprising:
administering to the subject, a composition comprising an effective amount of the naïve human induced pluripotent stem cells (N-hiPSC), wherein the N-hiPSC differentiate and revascularize the subject's ischemic retina, thereby treating the ischemic retina,
wherein the N-hiPSC are obtainable by steps comprising contacting a human induced pluripotent stem cell (hiPSC) with a composition comprising a leukemia inhibitory factor (LIF) and at least one or more agents which inhibit one or more signaling pathways to produce the N-hiPSC.

### Claim 2

A method of treating an ischemic retina of a subject in need thereof, comprising:
contacting a human induced pluripotent stem cell (hiPSC) with a composition comprising a leukemia inhibitory factor (LIF) and at least one or more agents which inhibit one or more signaling pathways to produce a naïve human induced pluripotent stem cell (N-hiPSC);
administering to the subject, a composition comprising an effective amount of the naïve human induced pluripotent stem cells (N-hiPSC), wherein the N-hiPSC differentiate and revascularize the subject's ischemic retina, thereby
treating the ischemic retina.

### Claim 3 (depends on 1)

The method of claim 1, wherein the one or more agents comprise simultaneous uses of inhibitors of tankyrase, mitogen-activated protein kinase kinase (MEK), Glycogen Synthase Kinase 3-β (GSK3β) or signaling pathways thereof.

### Claim 4 (depends on 3)

The method of claim 3, wherein a tankyrase inhibitor comprises: XAV939, IWR-1, G007-LK, JW55, AZ1366, JW 74, NVP-TNKS656 or combinations thereof.

### Claim 5 (depends on 3)

The method of claim 3, wherein a GSK3β inhibitor comprises: 6-[[2-[[4-(2,4-Dichlorophenyl)-5-(5-methyl-1H-imidazol-2-yl)-2-pyrimidinyl]amino]ethyl]amino]-3-pyridinecarbonitrile (CHIR 99021), 5-Ethyl-7,8-dimethoxy-1H-pyrrolo[3,4-c]isoquinoline-1,3(2H)-dione (3F8), 1-(7-Methoxyquinolin-4-yl)-3-[6-(trifluoromethyl)pyridin-2-yl]urea (A 1070722), N6-[2-[[4-(2,4-Dichlorophenyl)-5-(1H-imidazol-1-yl)-2-pyrimidinyl]amino]ethyl]-3-nitro-2,6-pyridinediamine (CHIR 98014), lithium chloride (LiCl), 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), 5-iodo-indirubin-3′-monoxime (I3′M) and N-(4-methoxybenzyl)-N′-(5-nitro-1,3-thiazol-2-yl)urea (AR-A014418) or combinations thereof.

### Claim 6 (depends on 3)

The method of claim 3, wherein MEK inhibitor comprises: PD032590, CI-1040 (PD184352), cobimetinib (GDC-0973, XL518), Selumetinib (AZD6244), MEK162, AZD8330, TAK-733, GDC-0623, Refametinib (RDEA119; BAY 869766), Pimasertib (AS703026), RO4987655 (CH4987655), RO5126766, WX-554, HL-085 or combinations thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the hiPSCs are derived from primed isogenic hiPSCs.

### Claim 8 (depends on 1)

The method of claim 1, wherein the hiPSC are derived from diabetic donor hiPSCs (DhiPSC) or non-diabetic donor hiPSCs.

### Claim 9 (depends on 1)

The method of claim 1 wherein the N-hiPSC are obtained by steps comprising contacting a human induced pluripotent stem cell (hiPSC) with a composition comprising a leukemia inhibitory factor (LIF) and at least one or more agents which inhibit one or more signaling pathways to produce the N-hiPSC

### Claim 10

A method of producing a vascular progenitor (VP) cell comprising:
contacting a human induced pluripotent stem cell (hiPSC) with a composition comprising a leukemia inhibitory factor (LIF) and at least one agent or a simultaneous combination of at least three agents which inhibit one or more signaling pathways to produce a naïve human induced pluripotent stem cell (N-hiPSC); and,
differentiating the N-hiPSC in vitro or by implantation in vivo.

### Claim 11 (depends on 10)

The method of claim 10, wherein the at least one agent is an inhibitor of poly-ADP-ribosyltransferase and signaling pathways thereof.

### Claim 12 (depends on 10)

The method of claim 10, wherein the at least one agent is an inhibitor of mitogen-activated protein kinase kinase (MEK) and signaling pathways thereof.

### Claim 13 (depends on 10)

The method of claim 10, wherein the at least one agent is an inhibitor of Glycogen Synthase Kinase 3 (GSK3) or signaling pathways thereof.

### Claim 14 (depends on 10)

The method of claim 10, wherein the composition comprising a combination of at least three agents comprises inhibitors of poly-ADP-ribosyltransferase, MEK, GSK3 and signaling pathways thereof.

### Claim 15 (depends on 10)

The method of claim 10, wherein the poly-ADP-ribosyltransferase is tankyrase.

### Claim 16 (depends on 10)

The method of claim 10, wherein the GSK3 is a GSK3β isoform.

### Claim 17 (depends on 15)

The method of claim 15, wherein a tankyrase inhibitor comprises: XAV939, IWR-1, G007-LK, JW55, AZ1366, JW 74, NVP-TNKS656 or combinations thereof.

### Claim at position 18

18-25. (canceled)

### Claim 26

A composition comprising an effective amount of naïve human induced pluripotent stem cells (N-hiPSCs) wherein the N-hiPSCs are tankyrase inhibitor regulated.

### Claim 27 (depends on 26)

The composition of claim 26, wherein the hiPSC is reprogrammed from donor diabetic or donor non-diabetic fibroblasts.

### Claim at position 21

28-29. (canceled)