Compositions and methods for the modulation of JNK proteins

• US 8,101,585 B2
• Filed: 08/06/2007
• Issued: 01/24/2012
• Est. Priority Date: 08/04/2006
• Status: Expired due to Fees

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Yu, Xing-Xian, Bhanot, Sanjay
• Primary Examiner(s): GIBBS, TERRA C
• Application Number:
  US11/834,672
• Publication Number:
  US 20080255030A1
• Time in Patent Office: 1,632 Days
• Field of Search: 536/23.1, 536/24.3, 536/24.33, 536/24.5, 514/44
• US Class Current: 514/44
• CPC Class Codes: A61K 31/07 Retinol compounds, e.g. vitamin A retinoic acids A61K31/203
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 3/10 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: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• 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

The invention provides compositions and methods for the treatment and diagnosis of diseases or disorders amenable to treatment through modulation of expression of a gene encoding a Jun N-terminal kinase 1 (JNK1 protein.

Claims

1. A method of reducing lipid levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antisense compound targeted to a JNK1 nucleic acid, thereby reducing lipid levels.

2. The method of claim 1, wherein the administering further results in a reduction in glucose levels, body weight, adiposity, or an increase in metabolic rate or insulin sensitivity or any combination thereof.

3. The method of claim 1, wherein the lipid levels are triglyceride or cholesterol or a combination thereof.

4. The method of claim 1, wherein the subject has Type 2 diabetes.

5. The method of claim 2, wherein the administering further results in reducing glucose levels or improving insulin sensitivity or both.

11. The method of claim 1, wherein the administering comprises parenteral administration.

12. The method of claim 11, wherein the parenteral administration comprises subcutaneous or intravenous administration.

13. The method of claim 1, wherein the antisense compound is complementary to SEQ ID NO:

87, 89, 90 or 91.

14. The method of claim 1, wherein the antisense compound is 12 to 30 nucleosides in length.

15. The method of claim 1, wherein the antisense compound is an antisense oligonucleotide.

16. The method of claim 1, wherein the antisense compound comprises at least one modified sugar moiety.

17. The method of claim 16, wherein the modified sugar moiety is a 2′

-O-methoxyethyl sugar moiety.

18. The method of claim 1, wherein the antisense compound comprises at least one modified internucleoside linkage.

19. The method of claim 18, wherein each internucleoside linkage of the antisense compound is a phosphorothioate internucleoside linkage.

20. The method of claim 1, wherein the antisense compound comprises at least one modified nucleobase.

21. The method of claim 1, wherein each cytosine of the antisense compound is a 5-methylcytosine.

22. The method of claim 1, wherein the antisense compound is a gapmer antisense oligonucleotide.

23. The method of claim 22, wherein the antisense compound is a gap-widened antisense oligonucleotide.

24. The method of claim 1, wherein the antisense oligonucleotide comprises a gap segment of ten 2′

-deoxynucleotides positioned between wing segments of five 2′

-O-methoxyethyl modified nucleosides.

25. The method of claim 1, wherein the subject has hyperlipidemia.

26. The method of claim 13, wherein the antisense compound has 100% complementarity to SEQ ID NO:

87, 89, 90 or 91.

27. The method of claim 25, wherein hyperlipidemia is hypercholesterolemia, hypertriglyceridemia or hyperfattyacidemia.

29. The method of claim 1, wherein the subject is obese.

30. The method of claim 1, wherein the subject has metabolic syndrome.

6. A method of treating obesity or metabolic syndrome in a subject comprising administering to said subject a lipid-lowering agent and a therapeutically effective amount of an antisense compound targeted to a JNK 1 nucleic acid, wherein said antisense compound targeted to said JNK 1 nucleic acid reduces lipid levels in said subject, thereby treating obesity or metabolic syndrome.

7. The method of claim 6, wherein said lipid-lowering agent is a HMG-CoA reductase inhibitor or a cholesterol absorption inhibitor.

8. The method of claim 7, wherein the HMG-CoA reductase inhibitor is a statin.

9. The method of claim 8, wherein the statin is atorvastatin, simvastatin, pravastatin, fluvastatin or rosuvastatin.

10. The method of claim 7, wherein the cholesterol absorption inhibitor is ezetimibe.

28. The method of claim 6, wherein the administering further results in reducing glucose levels or improving insulin sensitivity or both.