MODULATION OF GLUCOSE-6-PHOSPHATASE TRANSLOCASE EXPRESSION

• US 20110166065A1
• Filed: 03/10/2011
• Published: 07/07/2011
• Est. Priority Date: 04/21/2004
• Status: Active Grant

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Dobie, Kenneth W., Bhanot, Sanjay
• Granted Patent: US 8,258,114 B2
• Time in Patent Office: Days
• US Class Current: 514/6.5
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy

Abstract

Compositions and methods are provided for decreasing blood glucose levels in an animal, comprising administering to said animal an antisense inhibitor of glucose-6-phosphatase translocase expression alone or in combination with at least one glucose-lowering drug. Also provided are compositions and methods for treating diabetes and other metabolic disorders.

Claims

1. A method of lowering glucose levels in an animal, comprising administering to the animal a therapeutically effective amount of a glucose-6-phosphatase translocase specific inhibitor, wherein the glucose levels are reduced in the animal.

5. The method of claim 1, wherein the glucose is blood glucose.

6. The method of claims 1-3, wherein the animal is need of such treatment.

7. The method of claims 1-3, wherein said animal has condition selected from diabetes, type II diabetes, insulin resistance, insulin deficiency, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperfattyacidemia, liver steatosis, metabolic syndrome, cardiovascular disease, or a cardiovascular risk factor.

8. The method of claim 7, wherein said animal has a condition associated with metabolic syndrome.

9. The method of claims 1-3, wherein the glucose-6-phosphatase translocase specific inhibitor is a nucleic acid.

10. The method of claim 9, wherein the nucleic acid is a modified oligonucleotide.

11. The method of claim 10, wherein the modified oligonucleotide consists of 13 to 80 linked nucleosides.

12. The method of claim 10, wherein the modified oligonucleotide consists of 13 to 50 linked nucleosides.

13. The method of claim 10, wherein the modified oligonucleotide consists of 13 to 30 linked nucleosides.

14. The method of claim 10, wherein the modified oligonucleotide is a single-stranded oligonucleotide.

15. The method of claim 14, wherein the modified oligonucleotide has a nucleobase sequence that is 90% complementary to a human glucose-6-phosphatase translocase.

16. The method of claim 14, wherein the modified oligonucleotide has a nucleobase sequence that is 95% complementary to a human glucose-6-phosphatase translocase.

17. The method of claim 14, wherein the modified oligonucleotide has a nucleobase sequence that is 99% complementary to a human glucose-6-phosphatase translocase.

18. The method of claim 14, wherein the modified oligonucleotide has a nucleobase sequence that is 100% complementary to a human glucose-6-phosphatase translocase.

19. The method of claim 10, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

20. The method of claim 19, wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

21. The method of claim 10, wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.

22. The method of claim 21, wherein the modified sugar is a bicyclic sugar.

23. The method of claim 21, wherein the modified sugar comprises a 2′

-O-methoxyethyl group.

24. The method of claim 10, wherein at least one nucleoside of the modified oligonucleotide comprises a modified nucleobase.

25. The method of claim 24, wherein the modified nucleobase is a 5-methylcytosine.

26. The method of claim 10, wherein the modified oligonucleotide comprises:

a gap segment consisting of linked deoxy nucleosides;

a 5′

wing segment consisting of linked nucleosides;

a 3′

wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

27. The method of claim 10, further comprising the step of administering at least one additional glucose-lowering drug.

28. The method of claim 27 wherein the glucose-lowering drug is a hormone, a hormone mimetic, a sulfonylurea, a biguanide, a meglitinide, a thiazolidinedione, an alpha glucosidase inhibitor, or an antisense compound not targeted to glucose-6-phosphatase translocase.

29. The method of claim 28 wherein the hormone or hormone mimetic is insulin, GLP-1 or a GLP-1 analog.

30. The method of claim 29 wherein the GLP-1 analog is exendin-4 or liraglutide.

31. The method of claim 28 wherein the sulfonylurea is acetohexamide, chlorpropamide, tolbutamide, tolazamide, glimepiride, a glipizide, glyburide or a gliclazide.

32. The method of claim 28 wherein the biguanide is metformin.

33. The method of claim 28 wherein the meglitinide is nateglinide or repaglinide.

34. The method of claim 28 wherein the thiazolidinedione is pioglitazone, rosiglitazone or troglitazone.

35. The method of claim 28 wherein the alpha-glucosidase inhibitor is acarbose or miglitol.

2. A method of lowering triglycerides levels in an animal, comprising administering to the animal a therapeutically effective amount of a glucose-6-phosphatase translocase specific inhibitor, wherein the triglyceride levels are reduced in the animal.

4. The method of claim 2, wherein the triglycerides are circulating triglycerides.

3. A method of lowering cholesterol in an animal, comprising administering to the animal a therapeutically effective amount of a glucose-6-phosphatase translocase specific inhibitor, wherein the cholesterol is reduced in the animal.