Compositions and their uses directed to PTPR alpha

• US 8,158,598 B2
• Filed: 05/07/2007
• Issued: 04/17/2012
• Est. Priority Date: 05/05/2006
• Status: Expired due to Fees

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Bhanot, Sanjay, Murray, Susan F.
• Primary Examiner(s): McGarry, Sean
• Application Number:
  US12/299,610
• Publication Number:
  US 20100022619A1
• Time in Patent Office: 1,807 Days
• Field of Search: None
• US Class Current: 514/44.A
• 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 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• 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 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/345 having at least two different backbone modifications
• CPC Class Codes: C12N 2310/3521 Methyl

Abstract

Disclosed herein are compounds, compositions and methods for modulating the expression of PTPR.alpha. in a cell, tissue or animal. Also provided are methods of target validation. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders. Also provided are methods for the prevention, amelioration and/or treatment of airway hyperresponsiveness and pulmonary inflammation by administration of antisense compounds targeted to PTPR.alpha.

Claims

1. A method for the prevention, amelioration, or treatment of a disease or condition wherein indicators of the disease or condition comprise increased plasma glucose levels, increased plasma lipid levels, increased hepatic triglyceride levels, increased plasma transaminase levels, reduced hepatic function, reduced insulin sensitivity or combinations thereof comprising administering an antisense compound 12 to 35 linked nucleosides in length targeted to a nucleic acid molecule encoding human PTPR alpha to an individual in need of such intervention, wherein plasma glucose levels, plasma lipid levels, hepatic triglyceride levels or plasma transaminase levels are decreased, hepatic function or insulin sensitivity is improved or combinations thereof.

2. The method of claim 1 wherein the disease or condition is fatty liver disease and wherein administration of the compound results in a decrease in plasma lipid levels, a decrease in plasma transaminase levels, a decrease in hepatic triglyceride levels or combinations thereof.

3. The method of claim 1 wherein the disease or condition is type-2 diabetes and wherein administration of the compound results in a decrease in plasma glucose levels, an improvement in insulin sensitivity or combinations thereof.

4. The method of claim 1 wherein the disease or condition is metabolic syndrome and wherein administration of the compound results in a decrease in plasma glucose levels, a decrease in plasma lipid levels, a decrease in hepatic triglyceride levels, an improvement in insulin sensitivity, an improvement in hepatic function, a decrease in plasma transaminase levels or combinations thereof.

5. The method of claim 1 wherein the disease or condition comprises type-2 diabetes, fatty liver, metabolic syndrome or combinations thereof.

6. The method of claim 1 wherein the antisense compound optionally further comprises a complementary strand 15 to 35 nucleobases in length.

12. The method of claim 1, wherein the compound is at least 80% complementary to a target region of the nucleic acid encoding PTPRalpha.

13. The method of claim 1, wherein the compound optionally includes a complementary strand 15 to 35 nucleobases in length.

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

15. The compound of claim 14, wherein the compound has at least one modified internucleoside linkage, sugar moiety, or nucleobase.

16. The compound of claim 14, wherein the compound comprises a chimeric oligonucleotide.

17. The compound of claim 15, wherein the modified internucleoside linkage comprises a phosphorothioate linkage.

18. The compound of claim 15, wherein the at least one modified sugar moiety comprises a 2′

-MOE, a LNA, a 2′

-OMe, an ENA, a 2′

-F or combinations thereof.

19. The compound of claim 15, wherein the modified nucleobase comprises 5-methylcytosine.

20. The method of claim 12, wherein the compound is administered in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable penetration enhancer, carrier, or diluent.

7. A method for lowering blood glucose levels in an animal in need thereof by administering an antisense compound 12 to 35 nucleosides in length targeted to a nucleic acid molecule encoding human PTPR alpha.

8. A method for lowering triglyceride levels in an animal in need thereof by administering an antisense compound 12 to 35 nucleosides in length targeted to a nucleic acid molecule encoding human PTPR alpha.

9. The method of claim 8 wherein the triglyceride levels are lowered in the plasma.

10. The method of claim 8 wherein the triglyceride levels are lowered in the liver.

11. The method of claim 7, 8, 9 or 10 wherein the animal suffers from type-2 diabetes, fatty liver disease, obesity, metabolic syndrome of combinations thereof.