Methods of inducing regulated pancreatic hormone production in non-pancreatic islet tissues

• US 9,481,894 B2
• Filed: 07/14/2014
• Issued: 11/01/2016
• Est. Priority Date: 06/01/1999
• Status: Active Grant

• Current Assignee: Tel Hashomer Medical Research Infrastructure And Services Ltd.
• Original Assignee: Tel Hashomer Medical Research Infrastructure And Services Ltd.
• Inventors: Ferber, Sarah
• Primary Examiner(s): Singh, Anoop
• Assistant Examiner(s): Montanari, David A
• Application Number:
  US14/330,965
• Publication Number:
  US 20150017727A1
• Time in Patent Office: 841 Days
• Field of Search: 435/377
• US Class Current: 1/1
• CPC Class Codes: A61K 38/1709 from mammals
• 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: C12N 15/85 for animal cells
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/10343 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2830/008 cell type or tissue specific enhancer/promoter combination
• CPC Class Codes: C12N 2830/85 mammalian

Abstract

Disclosed are methods and pharmaceutical compositions for inducing pancreatic hormone production.

Claims

1. An in vitro method of increasing PDX-1 induction of a pancreatic islet cell phenotype or function in a population of human non-pancreatic primary cells, said method comprising the steps of:

(1) contacting a population of human non-pancreatic primary cells with a composition comprising a nucleic acid encoding a PDX-1 polypeptide, wherein said PDX-1 is ectopically expressed within said cell population,

(2) concurrently contacting said cell population with a composition comprising an effective amount of nicotinamide and epidermal growth factor; and

(3) measuring the expression levels of PDX-1 in the contacted cells of step (2),

wherein said concurrent contacting of said population with a composition comprising an effective amount of nicotinamide and epidermal growth factor increases PDX-1 induction of a pancreatic islet cell phenotype or function.

2. The method of claim 1, wherein said non-pancreatic cell population comprises a hepatic stem cell population.

3. The method of claim 1, wherein said non-pancreatic cell population comprises an adult cell population selected from the group consisting of a muscle cell population, a spleen cell population, a kidney cell population, a bone marrow cell population, a skin cell population, and a liver cell population.

4. The method of claim 1, wherein said increasing of PDX-1 induction of a pancreatic cell phenotype or function comprises at least two characteristics selected from the groups consisting of pancreatic islet specific gene expression, production of a pancreatic hormone, processing of a pancreatic hormone, storage of a pancreatic hormone and secretion of a pancreatic hormone.

5. The method of claim 4, wherein said pancreatic hormone is insulin, somatostatin, or glucagon, or any combination thereof.

6. The method of claim 4, wherein said islet cell gene expression profile in said population of human non-pancreatic primary cells comprises increased expression of PC1/3, insulin, glucagon or somatostatin, or any combination thereof, compared with expression in a control non-pancreatic cell population.

7. The method of claim 6, wherein said population of human non-pancreatic primary cells comprises sub-populations of cells, and wherein said islet cell gene expression of insulin, glucagon, or somatostatin, or any combination thereof, occurs in a same sub-population of cells.

8. The method of claim 6, wherein said population of human non-pancreatic primary cells comprises sub-populations of cells, and wherein said islet cell gene expression of insulin, glucagon, or somatostatin, or any combination thereof, occurs in different sub-populations of cells.

9. The method of claim 4, wherein insulin secretion is glucose-regulated.