Modulation of HIF1α and HIF2α expression
Compounds, compositions and methods are provided for modulating the expression of HIF1α and/or HIF2α. The compositions comprise oligonucleotides, targeted to nucleic acid encoding HIF1α and HIF2α. Methods of using these compounds for modulation of HIF1α and/or HIF2α expression and for diagnosis and treatment of disease associated with expression of HIF1α and/or HIF2α are provided.
1. A compound comprising a chimeric oligonucleotide consisting of 8 to 80 linked nucleosides, wherein said oligonucleotide is fully complementary to the nucleotide sequence within the range of nucleotides 1139 to 1218 of SEQ ID NO: 4.
2. A compound comprising a chimeric oligonucleotide consisting of 8 to 80 linked nucleosides, wherein said oligonucleotide comprises an at least 8 consecutive nucleobase portion that is fully complementary to an equal length portion of the nucleotide sequence within the range of nucleotides 1151 to 1230 of SEQ ID NO: 4, and wherein said chimeric oligonucleotide is fully complementary to SEQ ID NO: 4 .
3. The compound of claim 1 or 2 , wherein the oligonucleotide comprises 12 to 50 linked nucleosides.
4. The compound of claim 1 or 2 , wherein the oligonucleotide comprises 15 to 30 linked nucleosides.
5. A composition comprising the compound of claim 1 or 1 with a pharmaceutically acceptable carrier.
6. A method of inhibiting the expression of HIF1α in cells or tissues comprising contacting said cells or tissues with the compound of claim 1 or 2 , so that expression of HIF1α is inhibited.
7. A method of treating an animal having a disease or condition associated with HIF1α comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of claim 1 or 2 , so that expression of HIF1α is inhibited.
8. The compound of claim 3 , consisting of a single-stranded modified oligonucleotide.
9. The compound of claim 8 , wherein at least one internucleoside linkage is a modified internucleoside linkage.
10. The compound of claim 9 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
11. The compound of claim 8 , wherein at least one nucleoside comprises a modified sugar.
12. The compound of claim 11 , wherein at least one modified sugar is a bicyclic sugar.
13. The compound of claim 11 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl or a 4′-(CH 2 ) n ,-O-2′ bridge, wherein n is 1 or 2.
14. The compound of claim 8 , wherein at least one nucleoside comprises a modified nucleobase.
15. The compound of claim 14 , wherein the modified nucleobase is a 5-methylcytosine.
16. The compound of claim 3 , wherein the chimeric oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
17. The compound of claim 16 , wherein the chimeric oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
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 cytosine in said chimeric oligonucleotide is a 5-methylcytosine, and wherein each internucleoside linkage of said chimeric oligonucleotide is a phosphorothioate linkage.
18. The compound of claim 17 , wherein the chimeric oligonucleotide consists of 20 linked nucleosides.