Modulation of HIF1 beta expression

• US 20060252720A1
• Filed: 08/25/2005
• Published: 11/09/2006
• Est. Priority Date: 08/25/2004
• Status: Active Grant

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Marcusson, Eric G., Dobie, Kenneth W., Henry, Scott, Kim, Youngsoo
• Granted Patent: US 7,618,947 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 2310/11 Antisense
• 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 HIF1-beta. The compositions comprise oligonucleotides, targeted to nucleic acid encoding HIF1-beta. Methods of using these compounds for modulation of HIF1-beta expression and for diagnosis and treatment of diseases and conditions associated with expression of HIF1-beta are provided.

Claims

1. An antisense oligonucleotide 13 to 50 nucleobases in length which is specifically hybridizable with a nucleic acid molecule encoding human HIF1-beta, said antisense oligonucleotide comprising at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar moiety and a modified nucleobase, wherein said antisense oligonucleotide inhibits expression of human HIF1-beta.

2. The antisense oligonucleotide of claim 1 comprising 13 to 30 nucleobases in length.

3. The antisense oligonucleotide of claim 1, wherein the modified internucleoside linkage is a phosphorothioate linkage.

4. The antisense oligonucleotide of claim 1, wherein the modified sugar moiety is a 2′

-O-(2 methoxyethyl) moiety.

5. The antisense oligonucleotide of claim 1, wherein the modified nucleobase is a 5-methyl cytosine.

6. The antisense oligonucleotide of claim 1 which is a chimeric oligonucleotide.

7. The chimeric antisense oligonucleotide of claim 6 having a first region comprising 2′

-deoxynucleotides and second and third regions flanking said first region, comprising at least one 2′

-O-(2-methoxyethyl) nucleotide.

8. The chimeric antisense oligonucleotide of claim 7, wherein said first region is ten 2′

-deoxynucleotides in length and said second and third regions are each five nucleotides in length.

9. The chimeric antisense oligonucleotide of claim 8 further comprising a phosphorothioate internucleoside linkage at each position.

10. A pharmaceutical composition comprising the antisense oligonucleotide of claim 1 and a pharmaceutically acceptable carrier or diluent.

11. A method of inhibiting expression of human HIF1-beta in cells or tissues, comprising contacting said cells or tissues with the antisense oligonucleotide of claim 1, such that expression of human HIF1-beta is inhibited.

12. A method of inhibiting expression of a HIF1-beta regulated gene in a cell or tissue comprising contacting said cells or tissues with the antisense oligonucleotide of claim 1, such that expression of the HIF1-beta regulated gene is inhibited.

13. The method of claim 12, wherein the HIF1-beta regulated gene is selected from the group consisting of VEGF, GLUT-1, PGK-1, PAI-1 and Epo.

14. A method of treating an animal having a disease or condition associated with HIF1-beta comprising administrating to said animal a therapeutically or prophylactically effective amount of the composition of claim 10 so that expression of HIF1-beta is inhibited.

15. The method of claim 14, wherein the disease or condition is a hyperproliferative disorder.

16. The method of claim 15, wherein the hyperproliferative disorder is cancer.

17. The method of claim 15, wherein the hyperproliferative disorder is an angiogenic disorder.

18. The method of claim 17, wherein the angiogenic disorder is an ocular disorder.

19. The method of claim 18, wherein the ocular disorder is selected from the group consisting of macular degeneration, diabetic retinopathy, macular edema and retinopathy of prematurity.

20. A method of preventing or inhibiting aberrant angiogenesis in an animal, comprising administering to said an animal an antisense oligonucleotide of claim 1 such that aberrant angiogenesis is prevented or inhibited.