# US 10,369,162 B2 · Pharmaceutical composition including migratory factor for guiding pluripotent stem cells to damage

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- Number: US 10,369,162 B2
- Document ID: US10369162B2
- Status: Granted
- Kind: B2
- Application number: 15/642,534
- Filed: 2017-07-06
- Published: 2017-10-26
- Granted: 2019-08-06
- Earliest claimed: 2013-03-01
- Assignees: Clio, Inc.; Tohoku University; National University Corporation Nagoya University
- Applicants: Clio, Inc.; Tohoku University; National University Corporation Nagoya University
- Inventors: Mari Dezawa; Yoshinori Fujiyoshi; Masanori Yoshida
- Web page: https://patentgrep.com/patent/US10369162B2

## CPC

- A61K 31/661: Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion {or mevinphos}
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/4164: 1,3-Diazoles
- A61K 31/417: Imidazole-alkylamines, e.g. histamine, phentolamine
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- 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 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

## Abstract

The purpose of the present invention is to identify a migratory factor that guides pluripotent stem cells (Muse cells) useful in new medical applications to damage, and to provide a pharmaceutical composition that includes the migratory factor for promoting tissue regeneration in regenerative medicine that makes use of Muse cells. In the present invention, a receptor that is specifically expressed in Muse cells rather than non-Muse cells was identified, and it was confirmed that a ligand for this receptor can function as a migratory factor. In the present invention, sphingosine-1-phosphate (S1P) was identified as a migratory factor, and thus, the present invention pertains to a pharmaceutical composition for guiding pluripotent stem cells to damage, the composition including S1P as an active ingredient.

## Claims

### Claim 1

A method for activating migration of pluripotent stem cells, the method comprising: administering to a subject an agonist of sphingosine-1-phosphate receptor 2 as an active ingredient thereof, wherein the pluripotent stem cells are SSEA3-positive and CD105-positive and further have all of the following properties:
(i) low or absent telomerase activity;
(ii) ability to differentiate into cells of any of the three germ layers;
(iii) absence of demonstration of neoplastic proliferation; and
(iv) presence of self-renewal ability,
wherein the agonist of sphingosine-1-phosphate receptor 2 is 1-(2-(1-benzyl-2,5-dimethyl-1H-pyrrol-3-yl)-2-oxoethy)ppyrrolidine-2,5-dione.

### Claim 2

A method for enhancing guidance of pluripotent stem cells to a damaged site in the body, the method comprising: administering to a subject an agonist of sphingosine-1-phosphate receptor 2 as an active ingredient thereof, wherein the pluripotent stem cells are SSEA3-positive and CD105-positive and further have all of the following properties:
(i) low or absent telomerase activity;
(ii) ability to differentiate into cells of any of the three germ layers;
(iii) absence of demonstration of neoplastic proliferation; and
(iv) presence of self-renewal ability,
wherein the agonist of sphingosine-1-phosphate receptor 2 is 1-(2-(1-benzyl-2,5-dimethyl-1H-pyrrol-3-yl)-2-oxoethyl)pyrrolidine-2,5-dione.

### Claim 3

A method for enhancing therapeutic effects in tissue regeneration by pluripotent stem cells, the method comprising: administering to a subject an agonist of sphingosine-1-phosphate receptor 2 as an active ingredient thereof, wherein the pluripotent stem cells are SSEA3-positive and CD105-positive and further have all of the following properties:
(i) low or absent telomerase activity;
(ii) ability to differentiate into cells of any of the three germ layers;
(iii) absence of demonstration of neoplastic proliferation; and
(iv) presence of self-renewal ability,
wherein the agonist of sphingosine-1-phosphate receptor 2 is 1-(2-(1-benzyl-2,5-dimethyl-1H-pyrrol-3-yl)-2-oxoethyl)pyrrolidine-2,5-dione.

### Claim 4 (depends on 1, 2, 3)

The method of any one of claims 1 to 3, wherein the pluripotent stem cells are CD117-negative and CD146-negative.

### Claim 5 (depends on 1, 2, 3)

The method of any one of claims 1 to 3, wherein the pluripotent stem cells are CD117-negative, CD146-negative, NG2-negative, CD34-negative, vWF-negative and CD271-negative.

### Claim 6 (depends on 1, 2, 3)

The method of any one of claims 1 to 3, wherein the pluripotent stem cells are CD34-negative, CD117-negative, CD146-negative, CD271-negative, NG2-negative, vWF-negative, Sox10-negative, Snail-negative, Slug-negative, Tyrp1-negative and Dct-negative.