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 . An antisense compound 13 to 80 nucleobases in length targeted to a nucleic acid molecule encoding human transthyretin, wherein said compound inhibits the expression of human transthyretin mRNA by at least 10%.  
     
     
         2 . The antisense compound of  claim 1  comprising 13 to 50 nucleobases in length.  
     
     
         3 . The antisense compound of  claim 2  comprising 15 to 30 nucleobases in length.  
     
     
         4 . The antisense compound of  claim 1  comprising an oligonucleotide.  
     
     
         5 . The antisense compound of  claim 4  comprising a DNA oligonucleotide.  
     
     
         6 . The antisense compound of  claim 4  comprising an RNA oligonucleotide.  
     
     
         7 . The antisense compound of  claim 6  comprising a single-stranded RNA oligonucleotide.  
     
     
         8 . The antisense compound of  claim 4  comprising a chimeric oligonucleotide.  
     
     
         9 . The antisense compound of  claim 4  wherein at least a portion of said compound hybridizes with RNA to form an oligonucleotide-RNA duplex.  
     
     
         10 . The antisense compound of  claim 1  having at least one modified internucleoside linkage, sugar moiety, or nucleobase.  
     
     
         11 . The antisense compound of  claim 1  having at least one 2′-O-methoxyethyl sugar moiety.  
     
     
         12 . The antisense compound of  claim 1  having at least one phosphorothioate internucleoside linkage.  
     
     
         13 . The antisense compound of  claim 1  wherein at least one cytosine is a 5-methylcytosine.  
     
     
         14 . A method of inhibiting the expression of human transthyretin in a cell or tissue comprising contacting said cell or tissue with the antisense compound of  claim 1  so that expression of human transthyretin is inhibited.  
     
     
         15 . A method of screening for a modulator of human transthyretin, the method comprising the steps of: 
 contacting a preferred target segment of a nucleic acid molecule encoding human transthyretin with one or more candidate modulators of human transthyretin, and    identifying one or more modulators of human transthyretin expression which modulate the expression of human transthyretin.    
     
     
         16 . The method of  claim 15  wherein the modulator of transthyretin expression comprises an oligonucleotide, an antisense oligonucleotide, a DNA oligonucleotide, an RNA oligonucleotide, an RNA oligonucleotide having at least a portion of said RNA oligonucleotide capable of hybridizing with RNA to form an oligonucleotide-RNA duplex, or a chimeric oligonucleotide.  
     
     
         17 . A diagnostic method for identifying a disease state comprising identifying the presence of human transthyretin in a sample using at least one of the primers comprising SEQ ID NOs 5 or 6, or the probe comprising SEQ ID NO: 7.  
     
     
         18 . The antisense compound of  claim 1 , wherein said antisense compound has at least an 13 nucleobase portion of a sequence selected from the group consisting of SEQ ID NOs 15, 20, 24, 29, 30, 34, 35, 37, 39, 42, 44, 47, 49, 50, 53, 54, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87 and  88 .