Modulation of transthyretin expression

Abstract

Compounds, compositions and methods are provided for modulating the expression of transthyretin. The compositions comprise oligonucleotides, targeted to nucleic acid encoding transthyretin. Methods of using these compounds for modulation of transthyretin expression and for diagnosis and treatment of diseases and conditions associated with expression of transthyretin are provided.

1 . A method of inhibiting the expression of human transthyretin in a cell or tissue comprising contacting said cell or tissue in vitro with a compound comprising a modified oligonucleotide consisting of 8 to 80 nucleobases in length, wherein said oligonucleotide has a nucleobase sequence that is at least 95% complementary to a 3′ untranslated region of a nucleic acid molecule encoding human transthyretin recited in SEQ ID NO:4, and wherein said compound is double-stranded. 
     
     
         2 . The method of  claim 1 , wherein said modified oligonucleotide consists of 12 to 50 nucleobases in length. 
     
     
         3 . The method of  claim 1 , wherein said modified oligonucleotide consists of 15 to 30 nucleobases in length. 
     
     
         4 . The method of  claim 1 , wherein said modified oligonucleotide is a DNA oligonucleotide. 
     
     
         5 . The method of  claim 1 , wherein said modified oligonucleotide is an RNA oligonucleotide. 
     
     
         6 . The method of  claim 1 , wherein said modified oligonucleotide is a chimeric oligonucleotide. 
     
     
         7 . The method of  claim 1 , wherein at least a portion of said modified oligonucleotide hybridizes with RNA to form an oligonucleotide-RNA duplex. 
     
     
         8 . The method of  claim 1  having at least one modified internucleoside linkage, modified sugar, or modified nucleobase. 
     
     
         9 . The method of  claim 8 , wherein at least one sugar comprises a 2′-O-methoxyethyl. 
     
     
         10 . The method of  claim 8 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         11 . The method of  claim 8 , wherein at least one modified nucleobase is a 5-methylcytosine. 
     
     
         12 . A method of inhibiting the expression of human transthyretin in a cell or tissue comprising contacting said cell or tissue with a compound comprising a modified oligonucleotide consisting of 8 to 80 nucleobases in length, wherein said oligonucleotide has a nucleobase sequence that is at least 95% complementary to a 3′ untranslated region of a nucleic acid molecule encoding human transthyretin recited in SEQ ID NO:4, and wherein said compound is double-stranded 
     
     
         13 . The method of  claim 12 , wherein said modified oligonucleotide consists of 12 to 50 nucleobases in length. 
     
     
         14 . The method of  claim 12 , wherein said modified oligonucleotide consists of 15 to 30 nucleobases in length. 
     
     
         15 . The method of  claim 12 , wherein said modified oligonucleotide is a DNA oligonucleotide. 
     
     
         16 . The method of  claim 12 , wherein said modified oligonucleotide is an RNA oligonucleotide. 
     
     
         17 . The method of  claim 12 , wherein said modified oligonucleotide is a chimeric oligonucleotide. 
     
     
         18 . The method of  claim 12 , wherein at least a portion of said modified oligonucleotide hybridizes with RNA to form an oligonucleotide-RNA duplex. 
     
     
         19 . The method of  claim 12  having at least one modified internucleoside linkage, modified sugar, or modified nucleobase. 
     
     
         20 . The method of  claim 19 , wherein at least one sugar comprises a 2′-O-methoxyethyl. 
     
     
         21 . The method of  claim 19 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         22 . The method of  claim 19 , wherein at least one modified nucleobase is a 5-methylcytosine.