Modulation of HIF1α and HIF2α expression

• US 8,513,400 B2
• Filed: 12/18/2009
• Issued: 08/20/2013
• Est. Priority Date: 11/23/2002
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Ward, Donna T., Dobie, Kenneth W., Marcusson, Eric G., Freier, Susan M.
• Primary Examiner(s): VIVLEMORE, TRACY ANN
• Application Number:
  US12/642,534
• Publication Number:
  US 20110190370A1
• Time in Patent Office: 1,341 Days
• Field of Search: None
• US Class Current: 536/24.5
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 9/65586 at least one of the hetero rings does not contain nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy

Abstract

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.

Claims

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.

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′

-(CH₂)_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.

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.