Enhanced stem cell composition

Patent metadata

Field	Value
Publication number	US-9452186-B2
Application number	US-201214362386-A
Country	US
Kind code	B2
Filing date	Nov 29, 2012
Priority date	Dec 2, 2011
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

The invention provides improved methods for cell therapy. In particular, the invention provides therapeutic compositions of enhanced hematopoietic stem and progenitor cells having improved engraftment and homing properties, and methods of making the therapeutic compositions. The invention further provides methods of improving the efficacy of hematopoietic stem and progenitor cell transplantation including transplanting the therapeutic composition to subjects in need of hematopoietic system reconstitution.

First claim

The invention claimed is:

1. A human hematopoietic stem or progenitor cell
that has been contacted ex vivo with one or more agents that increase CXCR4 gene expression in the cell by at least about 30 fold in the contacted hematopoietic stem or progenitor cell compared to a hematopoietic stem or progenitor cell that has not been contacted ex vivo with one or more agents that increase CXCR4 gene expression.

2. The hematopoietic stem or progenitor cell of claim 1 , wherein the one or more agents comprise (i) one or more prostaglandin pathway agonists; and (ii) one or more glucocorticoids.

3. The hematopoietic stem or progenitor cell of claim 2 , wherein the one or more prostaglandin pathway agonists comprises PGE 2 or a PGE 2 analogue or derivative thereof.

4. The hematopoietic stem or progenitor cell of claim 2 , wherein the one or more glucocorticoids is selected from the group consisting of medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, cloprednol, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, fluclorolone, fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone, flumethasone pivalate, flunisolide, flunisolide hemihydrate, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin butyl, fluocortolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, meprednisone, 6amethylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide and ulobetasol.

5. The hematopoietic stem or progenitor cell of claim 1 , wherein the cell is obtained from bone marrow, umbilical cord blood, mobilized peripheral blood, Wharton's jelly, placenta, or fetal blood.

6. A therapeutic composition comprising a population of cells comprising human hematopoietic stem or progenitor cells contacted ex vivo with one or more agents under conditions sufficient to increase CXCR4 expression in the human hematopoietic stem or progenitor cells by at least about 30 fold compared to hematopoietic stem or progenitor cells that have not been contacted ex vivo with one or more agents that increase CXCR4 gene expression.

7. The therapeutic composition of claim 6 , wherein the one or more agents comprise (i) one or more prostaglandin pathway agonists and (ii) one or more glucocorticoids.

8. The therapeutic composition of claim 6 , wherein gene expression of CXCR4 is increased by at least about 40 fold in the contacted hematopoietic stem or progenitor cells compared to hematopoietic stem or progenitor cells that have not been contacted ex vivo with one or more agents that increase CXCR4 gene expression.

9. The therapeutic composition of claim 7 , wherein the one or more prostaglandin pathway agonists comprises PGE 2 or a PGE 2 analogue or derivative thereof.

10. The therapeutic composition of claim 7 , wherein the one or more glucocorticoids is selected from the group consisting of medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, cloprednol, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, fluclorolone, fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone, flumethasone pivalate, flunisolide, flunisolide hemihydrate, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin butyl, fluocortolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, meprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide and ulobetasol.

11. The therapeutic composition of claim 6 , wherein the hematopoietic stem or progenitor cells have been contacted for a time of at least about one hour with at least one of (i) one or more prostaglandin pathway agonists and (ii) one or more glucocorticoids.

12. The therapeutic composition of claim 6 , wherein the population of cells comprises at least about 0.01% and no more than about 50% of CD34+ cells.

13. The therapeutic composition of claim 6 , wherein the composition is not cultured.

14. A method of increasing hematopoietic stem or progenitor cell homing, engraftment, or reconstitution in a subject comprising administering to the subject a composition comprising a population of cells comprising human hematopoietic stem or progenitor cells wherein:
a) the hematopoietic stem or progenitor cells have been contacted ex vivo with one or more agents that increase CXCR4 gene expression in the cells; and
b) gene expression of CXCR4 is increased at least about 30 fold in the contacted hematopoietic stem or progenitor cells compared to hematopoietic stem or progenitor cells that have not been contacted ex vivo with one or more agents that increase CXCR4 gene expression in the cells.

15. The method of claim 14 , wherein the one or more agents comprise (i) one or more prostaglandin pathway agonists; and (ii) one or more glucocorticoids.

16. The method of claim 14 , wherein the hematopoietic stem or progenitor cells are obtained from bone marrow, umbilical cord blood, mobilized peripheral blood, Wharton's jelly, placenta, or fetal blood.

17. The method of claim 15 , wherein gene expression of CXCR4 is increased by at least about 40 fold in the contacted hematopoietic stem or progenitor cells compared to hematopoietic stem or progenitor cells that have not been contacted ex vivo with one or more agents that increase CXCR4 gene expression.

18. The method of claim 15 , wherein the prostaglandin pathway agonist comprises PGE 2 or a PGE2 analogue or derivative thereof.

19. The method of claim 15 , wherein the one or more glucocorticoids are selected from the group consisting of medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, cloprednol, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, desoxy

Assignees

• Fate Therapeutics Inc

Inventors

• Shoemaker Dan
• Robbins David
• Mendlein John D
• Desponts Caroline

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title