Antisense modulation of PTP1B expression
Compounds, compositions and methods are provided for modulating the expression of PTP1B. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding PTP1B. Methods of using these compounds for modulation of PTP1B expression and for treatment of diseases associated with expression of PTP1B are provided.
1. A compound comprising an oligonucleotide consisting of 12 to 30 linked nucleosides having at least an 8-contiguous nucleobase portion of SEQ ID NO: 166 or pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein said portion of SEQ ID NO: 166 is targeted to a segment of a nucleic acid molecule encoding PTP1B (SEQ ID NO: 3), the target segment comprising nucleotides 951 to 971.
3. The compound of claim 1 , wherein said pharmaceutically acceptable salt is a sodium salt.
4. The compound of claim 1 wherein the oligonucleotide comprises at least one modified internucleoside linkage.
5. The compound of claim 4 wherein the modified internucleoside linkage is a phosphorothioate linkage.
6. The compound of claim 1 wherein the oligonucleotide comprises at least one modified sugar moiety.
7. The compound of claim 6 wherein the modified sugar moiety is a 2′-O-(2-methoxyethyl) moiety.
8. The compound of claim 1 wherein the oligonucleotide comprises at least one modified nucleobase.
9. The compound of claim 8 wherein the modified nucleobase is a 5-methylcytosine.
10. The compound of claim 1 wherein the oligonucleotide is a chimeric oligonucleotide.
11. The compound of claim 5 wherein each internucleoside linkage of said antisense oligonucleotide is a phosphorothioate.
12. The compound of claim 7 wherein said oligonucleotide is flanked on both the 5′ and 3′ ends with at least one 2′-O-(2-methoxyethyl) nucleotides.
13. The compound of claim 9 wherein each cytosine in said antisense oligoucleotide is a 5-methylcytosine.
14. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
15. The composition of claim 14 further comprising a colloidal dispersion system.
16. The composition of claim 14 wherein the compound is an antisense oligonucleotide.
17. A method of inhibiting the expression of human PTP1B in cells or tissues comprising contacting said cells or tissues with the compound of claim 1 , whereby the expression of human PTP1B is inhibited.
18. An antisense oligonucleotide comprising the nucleobase sequence of SEQ ID NO: 166 wherein a ten deoxynucleotide region of said oligonucelotide is flanked on both the 5′ and 3′ ends with at least one 2′-O-(2-methoxyethyl) nucleotides, and wherein each internucleoside linkage of said oligonucleotide is a phosphorothioate and wherein each cytosine is a 5-methylcytosine.
19. A pharmaceutical composition comprising the antisense oligonucleotide of claim 18 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier, diluent, or excipient.
20. The pharmaceutical composition of claim 19 wherein said salt is a sodium salt.
21. A method of inhibiting the expression of PTP1B in cells or tissues comprising contacting said cells or tissues with the pharmaceutical composition of claim 19 , whereby the expression of human PTP1B is inhibited.
22. A compound comprising an oligonucleotide consisting of 12 to 30 linked nucleosides or pharmaceutically acceptable salt thereof, targeted to a target segment of a nucleic acid molecule encoding human PTP1B (SEQ ID NO: 3), the target segment comprising nucleotides 951-971.
23. A compound comprising an oligonucleotide consisting of 8 to 50 linked nucleosides having at least an 8-contiguous nucleobase portion of SEQ ID NO: 166 or pharmaceutically acceptable salt thereof.
24. A compound comprising an oligonucleotide consisting of 8 to 50 linked nucleosides or pharmaceutically acceptable salt thereof, complementary within a target segment of a nucleic acid molecule encoding human PTP1B (SEQ ID NO: 3), the target segment consisting of nucleotides 951-971.
25. The antisense compound of claim 2 , wherein said portion of SEQ ID NO: 166 is complementary within a segment of a nucleic acid molecule encoding PTP1B (SEQ ID NO: 3), the target segment consisting of nucleotides 951 to 971.
26. The antisense compound of claim 12 wherein said antisense oligonucleotide is flanked on both the 5′ and 3′ ends with five 2′-O-(2-methoxyethyl) nucleotides.
27. The antisense oligonucleotide of claim 18 wherein said antisense oligonucleotide is flanked on both the 5′ and 3′ ends with five 2′-O-(2-methoxyethyl) nucleotides.
28. The compound of claim 1 , wherein the oligonucleotide is a single stranded oligonucleotide.