Methods of treating ischemia

Patent metadata

Field	Value
Publication number	US-10111907-B2
Application number	US-201214362385-A
Country	US
Kind code	B2
Filing date	Nov 29, 2012
Priority date	Dec 2, 2011
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

The invention provides compositions comprising stem and/or progenitor cells that have been treated to enhance the therapeutic properties of the cells for treating ischemia. In particular, the present invention relates to the use of stem and/or progenitor cells having enhanced therapeutic properties to treat an ischemic tissue, a tissue damaged by ischemia, or at least one symptom associated with an ischemic tissue or a tissue damaged by ischemia.

First claim

We claim:

1. A method of increasing stem or progenitor cell homing to an ischemic tissue or a tissue damaged by ischemia, comprising:
(a) treating stem or progenitor cells ex vivo with a prostaglandin pathway agonist and a glucocorticoid; and
(b) administering a composition comprising the treated stem or progenitor cells to a subject having an ischemic tissue or a tissue damaged by ischemia.

2. A method of treating a subject having an ischemic tissue or a tissue damaged by ischemia comprising: administering a therapeutically effective amount of a composition comprising stem or progenitor cells treated ex vivo with a prostaglandin pathway agonist and a glucocorticoid.

3. A method of ameliorating at least one symptom associated with an ischemic tissue or a tissue damaged by ischemia in a subject comprising: administering a therapeutically effective amount of a composition comprising stem or progenitor cells treated ex vivo with a prostaglandin pathway agonist and a glucocorticoid.

4. The method according to any one of claims 1 to 3 , wherein the treatment of the stem or progenitor cells is sufficient to increase the percent (%) migration in an SDF-1 transwell migration assay at least two fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells.

5. The method of any one of claims 1 to 3 , wherein:
a) the stem or progenitor cells have been treated at a temperature of about 22° C. to about 37° C. for a period of time of less than about 24 hours;
b) the stem or progenitor cells have been treated at a temperature of about 22° C. to about 37° C. for a time of about one to about four hours; or
c) the stem or progenitor cells have been treated at a temperature of about 37° C. for a time of about 4 hours.

6. The method of any one of claims 1 to 3 , wherein:
a) the stem or progenitor cells are embryonic stem cells;
b) the stem or progenitor cells are adult stem cells;
c) the stem or progenitor cells are selected from the group consisting of: endothelial stem or progenitor cells, mesodermal stem or progenitor cells, and ectodermal stem or progenitor cells;
d) the stem or progenitor cells are selected from the group consisting of: mesenchymal stem or progenitor cells, hematopoietic stem or progenitor cells, placental stem or progenitor cells, umbilical cord stem or progenitor cells, bone marrow stem cells, and Wharton's jelly stem or progenitor cells;
e) the stem or progenitor cells are hematopoietic stem or progenitor cells;
f) the stem or progenitor cells are isolated from peripheral blood, bone marrow, umbilical cord blood, Wharton's jelly, placenta, or fetal blood;
g) the stem or progenitor cells are CD34+ cells;
h) the stem or progenitor cells are, or have been, expanded ex vivo prior to the treatment of the cells;
i) the stem or progenitor cells are allogeneic or autologous;
j) the stem or progenitor cells are allogeneic and have a complete or partial HLA-match with the patient;
k) the stem or progenitor cells are not matched with the patient;
l) the stem or progenitor cells are xenogeneic; or
m) the stem or progenitor cells are washed to substantially remove the prostaglandin pathway agonist or glucocorticoid in the composition, prior to administration of the composition to the subject.

7. The method of any one of claims 1 to 3 , wherein:
a) the prostaglandin pathway agonist is selected from the group consisting of: a prostaglandin, a prostaglandin EP2 receptor agonist, a prostaglandin EP4 receptor agonist and an agent having 16,16-dimethyl PGE2 (dmPGE2) activity;
b) the prostaglandin pathway agonist is selected from the group consisting of: prostaglandin E 2 (PGE 2 ), and dmPGE 2 ;
c) the glucocorticoid is selected from the group consisting of: 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, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, fluclorolone, fluclorolone acetonide, fludroxycortide, 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, medrysone, 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;
d) the glucocorticoid is selected from the group consisting of: medrysone, hydrocortisone, alclometasone, dexamethasone, methylprednisolone, triamcinolone or Cortisol; or
e) the prostaglandin pathway agonist is PGE 2 or dmPGE 2 or an analogue thereof, and the glucocorticoid is medrysone or dexamethasone.

8. The method of any one of claims 1 to 3 , wherein:
a) expression of one or more genes associated with increased homing of the stem or progenitor cells to the ischemic tissue or tissue damaged by ischemia, is increased at least two fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells, wherein the one or more genes is selected from the group consisting of: CXCR4, hyaluronan synthase 1 (HAS1), GTP-binding protein GEM (GEM), dual specificity protein phosphatase 4 (DUSP4), amphiregulin (AREG), Nuclear receptor related 1 protein (NR4A2), renin (REN), cAMP-responsive element modulator (CREM), collagen, type I, alpha 1 (COL1A1), and Fos-related antigen 2 (FOSL2);
b) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about five fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;
c) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about ten fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;
d) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about twenty fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;
e) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about fifty fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;
f) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about sixty fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;
g) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about seventy fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;
h) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about eighty fold in the treated stem or progenitor ce

Assignees

• Fate Therapeutics Inc

Inventors

• Shoemaker Dan
• Multani Pratik S
• Mendlein John D
• Robbins David

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P5/44

  Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title