Antisense modulation of stearoyl-CoA desaturase expression

Abstract

Antisense compounds, compositions and methods are provided for modulating the expression of stearoyl-CoA desaturase. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding stearoyl-CoA desaturase. Methods of using these compounds for modulation of stearoyl-CoA desaturase expression and for treatment of diseases associated with expression of stearoyl-CoA desaturase are provided.

1 . A compound 8 to 50 nucleobases in length targeted to a nucleic acid molecule encoding human stearoyl-CoA desaturase, wherein the compound specifically hybridizes with a nucleic acid molecule encoding human stearoyl-CoA desaturase and inhibits the expression of human stearoyl-CoA desaturase.  
     
     
         2 . The compound according to  claim 1 , which is an antisense oligonucleotide.  
     
     
         3 . The compound according to  claim 2 , which hybridizes to a sequence within a nucleic acid molecule encoding human stearoyl-CoA desaturase SEQ ID NO: 3, provided that said sequence does not include nucleotide sequences spanning 70 through nucleotide 91, nucleotide 242 through nucleotide 262, or nucleotide 860 through nucleotide 882 of SEQ ID NO: 3.  
     
     
         4 . The compound according to  claim 2 , wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.  
     
     
         5 . The compound according to  claim 4 , wherein the modified internucleoside linkage is a phosphorothioate linkage.  
     
     
         6 . The compound according to  claim 2 , wherein the antisense oligonucleotide comprises at least one modified sugar moiety.  
     
     
         7 . The compound according to  claim 6 , wherein the modified sugar moiety is a 2′-O-methoxyethyl sugar moiety.  
     
     
         8 . The compound according to  claim 2 , wherein the antisense oligonucleotide comprises at least one modified nucleobase.  
     
     
         9 . The compound according to  claim 8 , wherein the modified nucleobase is a 5-methylcytosine.  
     
     
         10 . The compound according to  claim 2 , wherein the antisense oligonucleotide is a chimeric oligonucleotide.  
     
     
         11 . The compound according to  claim 2 , wherein said antisense oligonucleotide inhibits expression of said human stearoyl CoA desaturase by at least 10% in a suitable assay.  
     
     
         12 . The compound according to  claim 2 , wherein said antisense oligonucleotide inhibits expression of said human stearoyl CoA desaturase by at least 90% in a suitable assay.  
     
     
         13 . The compound according to  claim 1 , wherein said compound comprises a sequence selected from the group consisting of SEQ ID NOS: 18, 19, 20, 23, 25, 26, 29, 30, 31, 33, 39, 43, 44, 83, 84, 85, 87, 88, 89, 91, 93, 94, 95, 97, 98, 100, 101, 102, 103, 105, 107, 108, 109, 110, 112, 113, 114, 115, 117, 118, 119, 120, 124, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 149, 150, 153, 154, 157, 158, 159, 160, 164, 165, 167, 168, 169, 188, 189, 197, 204, 207 and 210.  
     
     
         14 . The compound according to  claim 1 , wherein said compound comprises an antisense nucleic acid molecule that is specifically hybridizable with a 5′-untranslated region (5′ UTR) of stearoyl CoA desaturase.  
     
     
         15 . The compound according to  claim 1 , wherein said compound comprises an antisense nucleic acid molecule that is specifically hybridizable with a start codon region of stearoyl CoA desaturase.  
     
     
         16 . The compound according to  claim 1 , wherein said compound comprises an antisense nucleic acid molecule that is specifically hybridizable with a coding region of stearoyl CoA desaturase.  
     
     
         17 . The compound according to  claim 1 , wherein said compound comprises an antisense nucleic acid molecule that is specifically hybridizable with a stop codon region of stearoyl CoA desaturase.  
     
     
         18 . The compound according to  claim 1 , wherein said compound comprises an antisense nucleic acid molecule that is specifically hybridizable with a 3′-untranslated region (3′ UTR) of stearoyl CoA desaturase.  
     
     
         19 . A compound 8 to 50 nucleobases in length which specifically hybridizes with at least an 8-nucleobase portion of an active site on a nucleic acid molecule encoding human stearoyl-CoA desaturase.  
     
     
         20 . The compound according to  claim 19 , wherein said portion of said active site falls outside of nucleotide sequences spanning 70 through nucleotide 91, nucleotide 242 through nucleotide 262, or nucleotide 860 through nucleotide 882 of a nucleic acid molecule encoding human stearoyl-CoA desaturase SEQ ID NO: 3.  
     
     
         21 . A composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier or diluent.  
     
     
         22 . The composition according to  claim 21 , further comprising a colloidal dispersion system.  
     
     
         23 . The composition according to  claim 12 , wherein the compound is an antisense oligonucleotide.  
     
     
         24 . A method of inhibiting the expression of human stearoyl-CoA desaturase in cells or tissues comprising contacting the cells or tissues with the compound of  claim 1  so that expression of human stearoyl-CoA desaturase is inhibited.  
     
     
         25 . A method of treating a human having a disease or condition associated with human stearoyl-CoA desaturase comprising administering to the human a therapeutically or prophylactically effective amount of the compound of  claim 1  so that expression of human stearoyl-CoA desaturase is inhibited.  
     
     
         26 . The method according to  claim 25 , wherein the condition involves abnormal lipid metabolism.  
     
     
         27 . The method according to  claim 25 , wherein the condition involves abnormal cholesterol metabolism.  
     
     
         28 . The method according to  claim 25 , wherein the condition is atherosclerosis.  
     
     
         29 . The method according to  claim 25 , wherein the disease is cardiovascular disease.  
     
     
         30 . A method of screening for an antisense compound, the method comprising the steps of: 
 a. contacting a preferred target region of a nucleic acid molecule encoding human stearoyl-CoA desaturase with one or more candidate antisense compounds, said candidate antisense compounds comprising at least an 8-nucleobase portion which is complementary to said preferred target region, and    b. selecting for one or more candidate antisense compounds which inhibit the expression of a nucleic acid molecule encoding human stearoyl-CoA desaturase.    
     
     
         31 . A method for improving liver function in an animal having elevated liver enzymes comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of  claim 1  so that expression of stearoyl CoA desaturase is inhibited and thereby lowers liver enzyme levels.  
     
     
         32 . A method for treating an obese animal comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of  claim 1  so that expression of stearoyl CoA desaturase is inhibited, thereby reducing said animal's weight and appetite.  
     
     
         33 . A duplexed antisense compound comprising: 
 (a) a nucleobase sequence 8 to 80 nucleobases in length targeted to a nucleic acid molecule encoding stearoyl CoA desaturase with at least one natural or modified nucleobase forming an overhang at a terminus of said sequence; and    (b) the complementary sequence of said sequence (a) having optionally at least one natural or modified nucleobase forming an overhang at a terminus of said complementary sequence;    wherein said sequences (a) and (b), when hybridized, have at least one single-stranded overhang at at least one of terminus of said hybridized duplex, and wherein said duplex when interacted with a nucleic acid molecule encoding stearoyl CoA desaturase can modulate the expression of said reductase.