Modulation of hif1 beta expression

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.

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.