Antisense inhibition of PTEN expression

Abstract

Antisense compounds, compositions and methods are provided for modulating the expression of PTEN. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding PTEN. Methods of using these compounds for modulation of PTEN expression and for treatment of diseases and conditions associated with expression of PTEN are provided. Such conditions include diabetes and hyperproliferative conditions. Methods for decreasing blood glucose levels, inhibiting PEPCK expression, decreasing blood insulin levels, decreasing insulin resistance, increasing insulin sensitivity, decreasing blood triglyceride levels or decreasing blood cholesterol levels in an animal using the compounds of the invention are also provided. The animal is preferably a human; also preferably the animal is a diabetic animal.

What is claimed is:  
     
         1 . A compound 8 to 50 nucleobases in length targeted to a nucleic acid molecule encoding PTEN, wherein said compound specifically hybridizes with and inhibits the expression of PTEN.  
     
     
         2 . The compound of  claim 1  which is an antisense oligonucleotide.  
     
     
         3 . The compound of  claim 1  wherein the PTEN is human PTEN.  
     
     
         4 . The compound of  claim 1  wherein the PTEN is rodent PTEN.  
     
     
         5 . The compound of  claim 4  wherein the PTEN is mouse PTEN.  
     
     
         6 . The compound of  claim 4  wherein the PTEN is rat PTEN.  
     
     
         7 . The compound of  claim 1  which has a sequence comprising at least an 8-nucleobase portion of SEQ ID NO: 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 33, 34, 35, 36, 38, 40, 41, 42, 43, 44, 45, 46, 47.  
     
     
         8 . The compound of  claim 1  which has a sequence comprising at least an 8-nucleobase portion of SEQ ID NO: 48 or SEQ ID NO: 49.  
     
     
         9 . The compound of  claim 2  wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.  
     
     
         10 . The compound of  claim 9  wherein the modified internucleoside linkage is a phosphorothioate linkage.  
     
     
         11 . The compound of  claim 2  wherein the antisense oligonucleotide comprises at least one modified sugar moiety.  
     
     
         12 . The compound of  claim 11  wherein the modified sugar moiety is a 2′-O-methoxyethyl sugar moiety.  
     
     
         13 . The compound of  claim 2  wherein the antisense oligonucleotide comprises at least one modified nucleobase.  
     
     
         14 . The compound of  claim 13  wherein the modified nucleobase is a 5-methylcytosine.  
     
     
         15 . The compound of  claim 1  wherein the antisense oligonucleotide is a chimeric oligonucleotide.  
     
     
         16 . A compound which hybridizes to an active site on a nucleic acid molecule encoding PTEN.  
     
     
         17 . The compound of  claim 16  wherein the active site comprises a sequence complementary to at least an 8-nucleobase portion of SEQ ID NO: 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 33, 34, 35, 36, 38, 40, 41, 42, 43, 44, 45, 46, 47.  
     
     
         18 . The compound of  claim 1  wherein the nucleic acid molecule encoding PTEN encodes a mutant form of PTEN.  
     
     
         19 . A composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier or diluent.  
     
     
         20 . The composition of  claim 19  further comprising a colloidal dispersion system.  
     
     
         21 . The composition of  claim 19  wherein the compound is an antisense oligonucleotide.  
     
     
         22 . A method of inhibiting the expression of PTEN in cells or tissues comprising contacting said cells or tissues with the compound of  claim 1  so that expression of PTEN is inhibited.  
     
     
         23 . The method of  claim 22  wherein the cells or tissues are human cells or tissues.  
     
     
         24 . The method of  claim 22  wherein the cells or tissues are rodent cells or tissues.  
     
     
         25 . The method of  claim 24  wherein the rodent cells or tissues are mouse cells or tissues.  
     
     
         26 . The method of  claim 24  wherein the rodent cells or tissues are rat cells or tissues.  
     
     
         27 . The method of  claim 22  wherein the cells or tissues are liver, kidney or adipose cells or tissues.  
     
     
         28 . The method of  claim 22  wherein the PTEN is a mutant form of PTEN.  
     
     
         29 . A method of treating an animal having a disease or condition associated with PTEN comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of  claim 1  so that expression of PTEN is inhibited.  
     
     
         30 . The method of  claim 29  wherein the animal is a human.  
     
     
         31 . The method of  claim 29  wherein the disease or condition is a metabolic disease or condition.  
     
     
         32 . The method of  claim 29  wherein the disease or condition is diabetes.  
     
     
         33 . The method of  claim 29  wherein the disease or condition is Type 2 diabetes.  
     
     
         34 . The method of  claim 26  wherein the disease or condition is a hyperproliferative condition.  
     
     
         35 . The method of  claim 26  wherein the PTEN is a mutant form of PTEN.  
     
     
         36 . A method of decreasing blood glucose levels in an animal comprising administering to said animal the compound of  claim 1 .  
     
     
         37 . The method of  claim 36  wherein the animal is a human or a rodent.  
     
     
         38 . The method of  claim 36  wherein the blood glucose levels are plasma glucose levels or serum glucose levels.  
     
     
         39 . The method of  claim 36  wherein the animal is a diabetic animal.  
     
     
         40 . A method of inhibiting expression of PEPCK in cells or tissues comprising comprising contacting said cells or tissues with an inhibitor of PTEN so that expression of PEPCK is inhibited.  
     
     
         41 . The method of  claim 40  wherein the inhibitor of PTEN is a compound 8 to 50 nucleobases in length targeted to a nucleic acid molecule encoding PTEN, wherein said compound specifically hybridizes with and inhibits the expression of PTEN.  
     
     
         42 . A method of decreasing blood insulin levels in an animal comprising administering to said animal the compound of  claim 1 .  
     
     
         43 . The method of  claim 42  wherein the animal is a human or a rodent.  
     
     
         44 . The method of  claim 42  wherein the blood insulin levels are plasma insulin levels or serum insulin levels.  
     
     
         45 . The method of  claim 42  wherein the animal is a diabetic animal.  
     
     
         46 . A method of decreasing insulin resistance in an animal comprising administering to said animal the compound of  claim 1 .  
     
     
         47 . The method of  claim 46  wherein the animal is a human or a rodent.  
     
     
         48 . The method of  claim 46  wherein the animal is a diabetic animal.  
     
     
         49 . A method of increasing insulin sensitivity in an animal comprising administering to said animal the compound of  claim 1 .  
     
     
         50 . The method of  claim 49  wherein the animal is a human or a rodent.  
     
     
         51 . The method of  claim 49  wherein the animal is a diabetic animal.  
     
     
         52 . A method of decreasing blood triglyceride levels in an animal comprising administering to said animal the compound of  claim 1 .  
     
     
         53 . The method of  claim 52  wherein the animal is a human or a rodent.  
     
     
         54 . The method of  claim 52  wherein the animal is a diabetic animal.  
     
     
         55 . A method of decreasing blood cholesterol levels in an animal comprising administering to said animal the compound of  claim 1 .  
     
     
         56 . The method of  claim 55  wherein the animal is a human or a rodent.  
     
     
         57 . The method of  claim 55  wherein the animal is a diabetic animal.