Antisense modulation of PTP1B expression
View Patent ↗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.
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 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 modified oligonucleotide comprises:
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 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 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 , wherein the modified oligonucleotide comprises:
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 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 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 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 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 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 a nucleobase sequence consisting of SEQ ID NO: 26, wherein the modified oligonucleotide comprises:
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 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 a nucleobase sequence consisting of SEQ ID NO: 26 and comprising:
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 modified oligonucleotide is a 5-methylcytosine.
34. A compound consisting of a pharmaceutically acceptable salt of the single-stranded oligonucleotide of claim 33 .
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 a nucleobase sequence consisting of SEQ ID NO: 26 and comprising:
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 modified oligonucleotide is a 5-methylcytosine.