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1. (WO2018226797) MÉTHODE D'ÉLIMINATION DE CELLULES SOUCHES PLURIPOTENTES NON DIFFÉRENCIÉES
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

CLAIMS

What is claimed is:

1. A method for removing undifferentiated pluripotent stem cells from a sample comprising said cells, the method comprising exposing said samples to an effective amount of a cardiac glycoside.

2. The method of claim 1, wherein the cardiac glycoside is a compound of Formula (I) or a pharmaceutical acceptable salt thereof,


(I),

wherein L is a lactone group;

Ri, R4 and R5 are independently H or OH;

R2 is CH3 or CH2OH;

R3 is H or OH when the dotted line is absent or R3 is absent when the dotted line forms a double bond;

R4 is H or OH;

R5 is H or OH;

s is CH3; and

X is -OH or a glycoside of 1 to 6 sugar residues, each unsubstituted or substituted.

3. The method of claim 2, wherein the lactone group is an unsaturated, five- or six-membered lactone ring.

4. The method of claim 2, wherein the sugar residues are selected from the group consisting of rhamnose, glucose, digitoxose, digitalose, digginose, sarmentose, vallarose, and fructose.

5. The method of claim 2, wherein the sugar residues are unsubstituted or substituted with an acyl group, an amino group, a halogen group and/or an acylamido group.

6. The method of claim 2, wherein X is a glycoside of two digitoxose, one

acetyldigitoxose and one glucose; or X is a glycoside of three digitoxoses; or X is a glycoside of one rhamnose.

7. The method of claim 2, wherein the compound is selected from the group consisting



(ouabain);


(I)-4 (digitoxin);


(I)-5 (digitoxigenin);

and


(I)-7 (proscillaridin A).

8. The method of any one of claims 1 to 7, wherein the undifferentiated pluripotent stem cells are selected from the group consisting of embryonic stem cells (ESCs) and induced pluripotent stem cells (TPSC).

9. The method of any one of claims 1 to 8, wherein the undifferentiated pluripotent stem cells express a cell marker selected from the group consisting of Na /K -ATPase, Nanog, Oct4, Sox2, SSEA3, SSEA4, TRA-1-60, TRA-1-81 and a combination thereof.

10. The method of any one of claims 1 to 9, wherein the sample further comprises differentiated cells.

11. The method of claim 10, wherein the method further comprises culturing the differentiated cells to provide a cell population of said differentiated cells.

12. The method of claim 10, wherein the differentiated cells are mesenchymal stem cells (MSCs).

13. The method of claim 12, wherein the differentiated cells express a cell marker selected from the group consisting of consisting of CD44+, CD73+, CD90+, CD105+ and a combination thereof.

14 The method of claim 13, wherein the differentiated cells are CD45", CD34", CDl lb", CD 19", and/or HLA-DR".

15. The method of claim 10, wherein the differentiated cells are selected from the group consisting of osteoblasts, adipocytes, chondrocytes, endothelial cells, neuron cells and hepatocytes.

16. A method for preparing differentiated cells, comprising

(i) subjecting undifferentiated pluripotent stem cells to a condition suitable for differentiation to produce a cell population that comprises differentiated cells and

undifferentiated pluripotent stem cells;

(ii) removing the undifferentiated pluripotent stem cells by exposing the cell population to an effective amount of a cardiac glycoside; and

(iii) optionally culturing the remaining differentiated cells.

17. The method of claim 16, wherein the cardiac glycoside is a compound of Formula (I) or a pharmaceutical acceptable salt thereof as defined in any of claims 1 to 7.

18. The method of claim 16 or 17, wherein the undifferentiated pluripotent stem cells are selected from the group consisting of embryonic stem cells (ESCs) and induced pluripotent stem cells (TPSC).

19. The method of claim 16 or 17, wherein the differentiated cells are mesenchymal stem cells (MSCs).

20. The method of claim 19, wherein the differentiated cells express a cell marker selected from the group consisting of consisting of CD44+, CD73+, CD90+, CD105+ and a combination thereof.

21. The method of claim 20, wherein the differentiated cells are CD45", CD34", CDl lb", CD 19", and/or HLA-DR".

22. The method of claim 16 or 17, wherein the differentiated cells are selected from the group consisting of osteoblasts, adipocytes, chondrocytes, endothelial cells, neuron cells and hepatocyte.

23. A method for treating a subject in need of cell therapy, comprising administrating to the subject a cell population comprising differentiated cells wherein the cell population prior to administration to the subject has been exposed with a cardiac glycoside whereby undifferentiated cells present in the cell population, if any, are removed.

24. The method of claim 23, wherein the cardiac glycoside is a compound of Formula (I) or a pharmaceutical acceptable salt thereof as defined in any of claims 1 to 7.

25. The method of claim 23 or 24, wherein the undifferentiated pluripotent stem cells are selected from the group consisting of embryonic stem cells (ESCs) and induced pluripotent stem cells (IPSC).

26. The method of claim 23 or 24, wherein the differentiated cells are mesenchymal stem cells (MSCs).

27. The method of claim 26, wherein the differentiated cells express a cell marker

selected from the group consisting of consisting of CD44+, CD73+, CD90+, CD105+ and a combination thereof.

28. The method of claim 27, wherein the differentiated cells are CD45", CD34", CDl lb", CD 19", and/or HLA-DR".

29. The method of claim 23, wherein the differentiated cells are selected from the group consisting of osteoblasts, adipocytes, chondrocytes, endothelial cells, neuron cells and hepatocyte.

30. Use of a cardiac glycoside for manufacturing a composition for inducing cell death of undifferentiated pluripotent stem cells.

31. Use of claim 30, wherein the cardiac glycoside is a compound of Formula (I) or a pharmaceutical acceptable salt thereof as defined in any of claims 1 to 7.

32. The method of claim 30 or 31, wherein the undifferentiated pluripotent stem cells are selected from the group consisting of embryonic stem cells (ESCs) and induced pluripotent stem cells (TPSC).

33. A composition for cell therapy comprising a cardiac glycoside and a cell population that comprises differentiated cells.

34. The composition of claim 33, wherein the cardiac glycoside is a compound of Formula (I) or a pharmaceutical acceptable salt thereof as defined in any of claims 1 to 7.

35. The composition of claim 33 or 34, wherein the cell population prior to

administration to a subject in need has been exposed with the cardiac glycoside, whereby

undifferentiated cells present in the cell population, if any, are substantially removed.

36. A method for treating teratoma in a subject in need, comprising administering to the subject an effective amount of a cardiac glycoside.

37. The method of claim 36, wherein the cardiac glycoside is a compound of Formula (I) or a pharmaceutical acceptable salt thereof as defined in any of claims 1 to 7.