Antisense modulation of PTP1B expression

Abstract

Provided herein are methods, compounds, and compositions for reducing expression of PTP1B mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate metabolic disease, for example, diabetes, or a symptom thereof.

What is claimed is: 
     
       1. A method of treating diabetes in a subject comprising administering to the subject a pharmaceutical composition suitable for parenteral administration to an animal comprising an aqueous solution, said aqueous solution comprising:
 a pharmaceutically acceptable carrier or diluent; and 
 a single stranded modified oligonucleotide targeted to PTP1B consisting of 20 linked nucleosides having consisting of a nucleobase sequence consisting of SEQ ID NO: 26, or salt thereof, 
 wherein the carrier or diluent is sterile and the aqueous solution is suitably viscous for parenteral administration and wherein the composition is administered parenterally, thereby treating diabetes in the subject. 
 
     
     
       2. The method of  claim 1 , wherein the aqueous solution suitably viscous for parenteral administration has a viscosity level less than 40 centipoise (cP). 
     
     
       3. The method of  claim 2 , wherein the parenteral administration is subcutaneous injection. 
     
     
       4. The method of  claim 2 , wherein the parenteral administration is intravenous infusion. 
     
     
       5. The method of  claim 1 , wherein the 20 linked nucleosides of the single stranded modified oligonucleotide comprises consist of:
 a gap segment consisting of ten linked deoxynucleosides; 
 a 5′ wing segment consisting of five linked nucleosides; and 
 a 3′ wing segment consisting of five linked nucleosides; 
 wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine of the single stranded modified oligonucleotide is a 5-methylcytosine. 
 
     
     
       6. The method of  claim 5 , wherein the aqueous solution suitably viscous for parenteral administration has a viscosity level less than 40 centipoise (cP). 
     
     
       7. The method of  claim 6 , wherein the aqueous solution comprises the single stranded modified oligonucleotide targeted to PTP1B at a concentration of about 165-185 mg/mL. 
     
     
       8. The method of  claim 7 , wherein the aqueous solution has a temperature of about 25° C. 
     
     
       9. The method of  claim 8 , wherein the parenteral administration is subcutaneous injection. 
     
     
       10. The method of  claim 8 , wherein the parenteral administration is intravenous infusion. 
     
     
       11. The method of  claim 1 , wherein the pharmaceutically acceptable carrier or diluent is water. 
     
     
       12. The method of claim  5  11, wherein the 20 linked nucleosides of the single stranded modified oligonucleotide comprises consist of:
 a gap segment consisting of ten linked deoxynucleosides; 
 a 5′ wing segment consisting of five linked nucleosides; and 
 a 3′ wing segment consisting of five linked nucleosides; 
 wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine of the single stranded modified oligonucleotide is a 5-methylcytosine. 
 
     
     
       13. The method of  claim 12 , wherein the aqueous solution suitably viscous for parenteral administration has a viscosity level less than 40 centipoise (cP). 
     
     
       14. The method of  claim 13 , wherein the aqueous solution comprises the single stranded modified oligonucleotide targeted to PTP1B at a concentration of about 165-185 mg/mL. 
     
     
       15. The method of  claim 14 , wherein the aqueous solution has a temperature of about 25° C. 
     
     
       16. The method of  claim 15 , wherein the parenteral administration is subcutaneous injection. 
     
     
       17. The method of  claim 16 , wherein the parenteral administration is intravenous infusion. 
     
     
       18. The method of  claim 1 , wherein the subject is human. 
     
     
       19. The method of  claim 18 , wherein the diabetes is Type II diabetes. 
     
     
       20. The method of  claim 19 , wherein administering the compound composition decreases blood glucose levels in the human. 
     
     
       21. The method of  claim 12 , wherein the subject is human. 
     
     
       22. The method of  claim 21 , wherein the diabetes is Type II diabetes. 
     
     
       23. The method of  claim 22 , wherein administering the compound composition decreases blood glucose levels in the human. 
     
     
       24. The method of  claim 13 , wherein the subject is human. 
     
     
       25. The method of  claim 24 , wherein the diabetes is Type II diabetes. 
     
     
       26. The method of  claim 25 , wherein administering the compound composition decreases blood glucose levels in the human. 
     
     
       27. A method of decreasing blood glucose levels in a subject comprising administering to the subject a compound consisting of a single stranded modified oligonucleotide targeted to PTP1B consisting of 20 linked nucleosides having consisting of a nucleobase sequence consisting of SEQ ID NO: 26, wherein the 20 linked nucleosides of the single stranded modified oligonucleotide comprises consist of:
 a gap segment consisting of ten linked deoxynucleosides; 
 a 5′ wing segment consisting of five linked nucleosides; and 
 a 3′ wing segment consisting of five linked nucleosides; 
 wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine of the single stranded modified oligonucleotide is a 5-methylcytosine; and 
 wherein the compound is administered to the subject parenterally, thereby decreasing blood glucose levels in the subject. 
 
     
     
       28. The method of  claim 27 , wherein the subject is human. 
     
     
       29. The method of  claim 28 , wherein the human has diabetes. 
     
     
       30. The method of  claim 29 , wherein the diabetes is Type II diabetes. 
     
     
       31. The method of  claim 29 , wherein administering the compound treats diabetes. 
     
     
       32. The method of  claim 30 , wherein administering the compound treats diabetes. 
     
     
       33. A single stranded modified oligonucleotide consisting of 20 linked nucleosides having consisting of a nucleobase sequence consisting of SEQ ID NO: 26 and comprising, wherein the 20 linked nucleosides of the single stranded modified oligonucleotide consist of:
 a gap segment consisting of ten linked deoxynucleosides; 
 a 5′ wing segment consisting of five linked nucleosides; and 
 a 3′ wing segment consisting of five linked nucleosides; 
 wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine of the single stranded modified oligonucleotide is a 5-methylcytosine. 
 
     
     
       34. A compound consisting of comprising a pharmaceutically acceptable salt of the single-stranded a single stranded oligonucleotide of  claim 33  consisting of 20 linked nucleosides consisting of a nucleobase sequence consisting of SEQ ID NO: 26, wherein the 20 linked nucleosides of the single stranded modified oligonucleotide consist of:
 a gap segment consisting of ten linked deoxynucleosides; 
 a 5′ wing segment consisting of five linked nucleosides; and 
 a 3′ wing segment consisting of five linked nucleosides; 
 wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine of the single stranded modified oligonucleotide is a 5-methylcytosine. 
 
     
     
       35. The compound of  claim 34 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
       36. The compound of  claim 34 , wherein the pharmaceutically acceptable salt is a potassium salt. 
     
     
       37. A compound consisting of a sodium salt of a single stranded modified oligonucleotide consisting of 20 linked nucleosides having consisting of a nucleobase sequence consisting of SEQ ID NO: 26 and comprising, wherein the 20 linked nucleosides of the single stranded modified oligonucleotide consist of:
 a gap segment consisting of ten linked deoxynucleosides; 
 a 5′ wing segment consisting of five linked nucleosides; and 
 a 3′ wing segment consisting of five linked nucleosides; 
 wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; each internucleoside linkage is a phosphorothioate linkage; and each cytosine of the single stranded modified oligonucleotide is a 5-methylcytosine.