PEPTIDE THERAPY FOR HYPERGLYCEMIA

• US 20100331247A1
• Filed: 04/07/2010
• Published: 12/30/2010
• Est. Priority Date: 04/07/2009
• Status: Active Grant

• Current Assignee: Duke University
• Original Assignee: Duke University
• Inventors: Stephens, Samuel B., Schisler, Jonathan C., Newgard, Christopher B.
• Granted Patent: US 8,580,732 B2
• Time in Patent Office: Days
• US Class Current: 514/6.8
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10

Abstract

Methods of modulating blood glucose levels treating hyperglycemia and related complications and conditions by administration of a VGF biomolecule to a patient in need of such treatment are provided. Methods of enhancing insulin secretion from islet beta cells in a mammal exhibiting reduced insulin secretion by administration of a therapeutically effective amount of a VGF biomolecule are also provided.

Claims

1. A method of treating hyperglycemia comprising administering to a patient in need of the treatment a therapeutically effective amount of a VGF biomolecule.

2. The method of claim 1, wherein the hyperglycemia is secondary to Type II diabetes.

3. The method of claim 1, wherein the patient is capable of producing insulin.

4. The method of claim 1, wherein the patient comprises tissues resistant to the effects of insulin.

5. The method of claim 1, wherein the VGF biomolecule is a VGF polypeptide comprising

Peptide1-X-Peptide2-Z-Peptide3-J-Arg

wherein Peptide1 comprises a first sequence having at least about 80% identity with SEQ ID NO. 5 (TLQPP), Peptide2 comprises a second sequence having at least about 75% identity with SEQ ID NO. 6 (RRRH) and Peptide3 comprises a third sequence having at least about 80% identity with SEQ ID NO. 7 (HHALPP);

and

wherein X is from zero to five amino acids, Z is from zero to three amino acids and J is from zero to three amino acids.

6. The method of claim 5, wherein X is X_aa1X_aa2X_aa3 and X_aa1 is serine or alanine, X_aa2 is serine or alanine, and X_aa3 is serine or leucine, wherein Z is phenylalanine or tyrosine and wherein J is serine or alanine.

7. The method of claim 6, wherein the VGF polypeptide comprises SEQ ID NO:

5-X-SEQ ID NO;

6-Z-SEQ ID NO;

7-J-R (TLQPP-X-RRRH-Z-HHALPP-J-R).

8. The method of claim 6, wherein X is X_aa1X_aa2X_aa3 and X_aa1 is serine or alanine, X_aa2 is serine or alanine, and X_aa3 is serine or leucine, wherein Z is phenylalanine or tyrosine and wherein J is serine or alanine.

9. The method of claim 5, wherein the VGF polypeptide comprises SEQ ID NO. 8 or SEQ ID NO. 9.

10. The method of claim 1, wherein the VGF biomolecule is a polypeptide from 15 to 40 amino acids in length and comprises at least one of SEQ ID NO. 5 (TLQPP), SEQ ID NO. 6 (RRRH), and SEQ ID NO. 7 (HHALPP).

11. The method of claim 1, wherein the VGF biomolecule is a polypeptide having at least about 50 percent identity with SEQ ID NO. 8, and comprising a first sequence having at least about 80% identity with SEQ ID NO. 5 (TLPPQ), a second sequence having at least about 75% identity with SEQ ID NO. 6 (RRRH) and a third sequence having at least about 80% identity with SEQ ID NO. 7 (HHALPP).

12. The method of claim 1, wherein the VGF biomolecule is a polypeptide from about 10 to about 60 amino acids long.

13. The method of claim 1, wherein the VGF biomolecule is a polypeptide comprising a TLQP-21 polypeptide.

14. The method of claim 1, wherein glucose stimulated insulin secretion in the patient is increased after administering the VGF biomolecule.

15. The method of claim 1, wherein the blood glucose concentration in the patient decreases after administering the VGF biomolecule.

16. The method of claim 1, wherein islet beta cell mass or islet beta cell function in the patient is enhanced after administering the VGF biomolecule.

17. The method of claim 1, wherein the VGF biomolecule is a polynucleotide encoding a VGF polypeptide, wherein the polynucleotide is operably linked to a promoter that directs expression of the polynucleotide in islet beta cells of the patient and is comprised in a vector.

18. The method of claim 1, wherein administration of the VGF biomolecule provides chronic glycemic control in the patient.

19. The method of claim 1, wherein administration of the VGF biomolecule provides acute glycemic control in the patient in response to acute glycemic challenge.

20. The method of claim 2, further comprising treatment of complications or conditions associated with hyperglycemia.

21. The method of claim 1, further comprising administering metformin, a thiazolidinedione or a combination thereof.

22. The method of claim 1, wherein the VGF biomolecule is a polypeptide administered in an amount of at least about 0.01 mg/kg/day and less than about 150 mg/kg/day.

23. A method for modulating the blood glucose concentration in a pre-diabetic mammal comprising administering to the mammal a therapeutically effective amount of a VGF biomolecule.

24. The method of claim 23, wherein the VGF biomolecule is a polypeptide comprising

Peptide1-X-Peptide2-Z-Peptide3-J-Arg

wherein Peptide1 comprises a first sequence having at least about 80% identity with SEQ ID NO. 5 (TLQPP), Peptide2 comprises a second sequence having at least about 75% identity with SEQ ID NO. 6 (RRRH) and Peptide3 comprises a third sequence having at least about 80% identity with SEQ ID NO. 7 (HHALPP);

and

wherein X is from zero to five amino acids, Z is from zero to three amino acids and J is from zero to three amino acids.