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

• US 9,546,379 B2
• Filed: 07/07/2015
• Issued: 01/17/2017
• Est. Priority Date: 03/27/2014
• Status: Active Grant

• Current Assignee: Salk Institute for Biological Studies
• Original Assignee: Salk Institute for Biological Studies
• Inventors: Yoshihara, Eiji, Downes, Michael R., Atkins, Annette R., Evans, Ronald M., Yu, Ruth T.
• Primary Examiner(s): Singh, Anoop
• Assistant Examiner(s): Montanari, David A
• Application Number:
  US14/793,391
• Publication Number:
  US 20150368667A1
• Time in Patent Office: 560 Days
• Field of Search: 435/377
• US Class Current: 1/1
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61K 35/35 Fat tissue; Adipocytes; Stromal cells; Connective tissues adipose-derived stem cells A61K35/28; collagen A61K38/39
• CPC Class Codes: A61K 35/39 Pancreas; Islets of Langerhans Langerhans cells of epidermis A61K35/36
• CPC Class Codes: A61K 35/51 Umbilical cord; Umbilical cord blood; Umbilical stem cells
• CPC Class Codes: A61K 35/545 Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/70567 Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors
• CPC Class Codes: C07K 14/721 Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor
• CPC Class Codes: C12N 15/85 for animal cells
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2501/105 Insulin-like growth factors [IGF]
• CPC Class Codes: C12N 2501/115 Basic fibroblast growth factor (bFGF, FGF-2)
• CPC Class Codes: C12N 2501/392 Sexual steroids
• CPC Class Codes: C12N 2501/415 Wnt; Frizzeled
• CPC Class Codes: C12N 2506/02 from embryonic cells
• CPC Class Codes: C12N 2510/00 Genetically modified cells
• CPC Class Codes: C12N 2710/10032 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2710/10043 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 5/0676 : Pancreatic cells

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.

Claims

1. An in vitro method for differentiating a pancreatic β

-cell progenitor into a mature β

-cell comprising the step of;

contacting a pancreatic β

-cell progenitor cell which expresses PDX1 and insulin with a viral vector encoding estrogen-related receptor γ

(ERRγ

) in an amount sufficient to overexpress ERRγ

in the cell;

wherein said contacting differentiates the pancreatic β

-cell progenitor cell into a mature β

-cell which is capable of glucose-stimulated insulin secretion.

2. The method of claim 1, wherein the pancreatic β

-cell progenitor expresses one or more β

cell transcription factors selected from the group consisting of Nkx2.2, NeuroD1, Foxa2, Pax6, HNF4a MafA and Nkx6-1.

3. The method of claim 1, wherein the pancreatic β

-cell progenitor expresses one or more β

-cell markers selected from glucagon or somatostatin.

4. The method of claim 1, wherein the mature pancreatic β

-cell expresses 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.