Compositions and methods for treating type 1 and type 2 diabetes and related disorders

Patent metadata

Field	Value
Publication number	US-10912800-B2
Application number	US-201615359432-A
Country	US
Kind code	B2
Filing date	Nov 22, 2016
Priority date	Mar 27, 2014
Publication date	Feb 9, 2021
Grant date	Feb 9, 2021

Abstract

The invention features compositions comprising in vitro generated beta cells capable of glucose-stimulated insulin secretion, methods of inducing beta cell maturation from embryonic or induced pluripotent stem cell-derived beta-like cells, and methods of using in vitro generated beta cells for the treatment of type 1 diabetes, type 2 diabetes, or a related disorder.

First claim

What is claimed is:

1. A method of ameliorating hyperglycemia in a mammalian subject in need thereof, the method comprising:
administering to a mammalian subject having or suspected of having hyperglycemia an effective amount of mature mammalian β-like cells, which comprise a viral vector that overexpresses recombinant estrogen-related receptor gamma (ERRγ) in the cells and which secrete insulin upon glucose stimulation; and
reducing or normalizing blood glucose levels in the subject following administration of the mature mammalian β-like cells, thereby ameliorating the subject's hyperglycemia.

2. The method of claim 1 , wherein the mature mammalian β-like cells express one or more mRNA selected from the group consisting of Mafa, Pax6, NeuroD, GCK, CHGA, VAMP2, PC1/3, Glut2, Nkx6.1, GCG, SST, and U36B4.

3. The method of claim 1 , wherein the mature mammalian β-like cells are generated from mammalian β-cell progenitor cells derived from the subject.

4. The method of claim 1 , wherein the mature mammalian β-like cells are generated from mammalian β-cells not derived from the subject.

5. The method of claim 1 , wherein the viral vector is an adeno-associated viral vector (AAV).

6. A method of reducing elevated blood glucose levels in a mammalian subject with hyperglycemia, the method comprising: administering to a mammalian subject in need thereof an effective amount of mature mammalian β-like cells which comprise an viral vector that overexpresses recombinant estrogen-related receptor gamma (ERRγ) in the cells, and wherein the cells exhibit increased mitochondrial oxidative metabolism and secrete insulin upon glucose stimulation; and
reducing the subject's elevated blood glucose levels to a normal range following administration of said mature mammalian β-like cells.

7. The method of claim 6 , wherein the mature mammalian β-like cells express one or more mRNA selected from the group consisting of Mafa, Pax6, NeuroD, GCK, CHGA, VAMP2, PC1/3, Glut2, Nkx6.1, GCG, SST, and U36B4.

8. The method of claim 6 , wherein the mature mammalian β-like cells are generated from mammalian β-cells derived from the subject.

9. The method of claim 6 , wherein the mature mammalian β-like cells are generated from mammalian β-cells not derived from the subject.

10. A method of ameliorating hyperglycemia or reducing elevated blood glucose levels in a mammalian subject in need thereof, the method comprising:
(a) contacting mammalian β-cells which express PDX1 and insulin with a viral vector encoding estrogen-related receptor gamma (ERRγ) in an amount sufficient to overexpress ERRγ to obtain mature mammalian β-cells; and
(b) administering an effective amount of the mature mammalian β-cells of step (a) to a mammalian subject having hyperglycemia, wherein administration of the mature β-cells reduces or normalizes blood glucose levels in the mammalian subject, thereby ameliorating the subject's hyperglycemia and reducing the subject's elevated blood glucose levels.

11. The method of claim 10 , wherein the viral vector is an adeno-associated viral vector (AAV).

12. The method of claim 10 , wherein the mammalian β-cells express one or more β-cell transcription factors selected from the group consisting of Nkx2.2, NeuroD1, Foxa2, Pax6, HNF4a, MafA and Nkx6-1.

13. The method of claim 10 , wherein the mammalian β-cells express one or more β-cell markers selected from glucagon and somatostatin.

14. The method of claim 10 , wherein the mature mammalian β-cells express one or more mRNA selected from the group consisting of Mafa, Pax6, NeuroD, GCK, CHGA, VAMP2, PC1/3, Glut2, Nkx6.1, GCG, SST, and U36B4.

15. The method of claim 10 , wherein the mammalian β-cells are derived from the subject.

16. The method of claim 10 , wherein the mammalian β-cells are not derived from the subject.

17. The method of claim 1 , wherein the mature mammalian β-cells are administered in a composition comprising a pharmaceutically acceptable carrier, diluent, or excipient.

18. The method of claim 6 , wherein the mature mammalian β-cells are administered in a composition comprising a pharmaceutically acceptable carrier, diluent, or excipient.

19. The method of claim 10 , wherein the mature mammalian β-cells are administered in a composition comprising a pharmaceutically acceptable carrier, diluent, or excipient.

Assignees

• Salk Inst For Biological Studi

Inventors

• Evans Ronald M
• Yoshihara Eiji
• Downes Michael R
• Yu Ruth T
• Atkins Annette R

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C12N2506/02

  from embryonic cells · CPC title

• C07K14/70567

  Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors · CPC title

• C07K14/721

  Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor · CPC title

• C12N2501/392

  Sexual steroids · CPC title