Antisense modulation of fibroblast growth factor receptor 4 expression

Abstract

Provided herein are methods, compounds, and compositions for reducing expression of fibroblast growth factor receptor 4 (FGFR4) mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate a metabolic disease, or a symptom thereof.

1 . A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the linked nucleosides comprise at least 8 contiguous nucleobases of a sequence recited in SEQ ID NOs: 17, 45, 46, 70, 72, or 138. 
     
     
         2 - 7 . (canceled) 
     
     
         8 . The compound of  claim 1  wherein the modified oligonucleotide is a single-stranded oligonucleotide. 
     
     
         9 . (canceled) 
     
     
         10 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NO 1 or 2. 
     
     
         11 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO 1 or 2. 
     
     
         12 . The compound of  claim 1  wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         13 . The compound of  claim 12 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         14 . The compound of  claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar. 
     
     
         15 . The compound of  claim 14 , wherein the at least one modified sugar is a bicyclic sugar. 
     
     
         16 . The compound of  claim 15 , wherein each of the at least one bicyclic sugar comprises a 4′-CH2-N(R)—O-2′ bridge wherein R is, independently, H, C1-C12 alkyl, or a protecting group. 
     
     
         17 . The compound of  claim 15 , wherein each of the at least one bicyclic sugar comprises a 4′-CH(CH3)-O-2′ bridge. 
     
     
         18 . The compound of  claim 14 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl group. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The compound of  claim 1 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         22 . The compound of  claim 21 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         23 . The compound of  claim 1 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         24 . The compound of  claim 23 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides; and   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; and wherein each internucleoside linkage is a phosphorothioate linkage.   
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . The compound of  claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         28 . A composition comprising the compound of  claim 1  or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent. 
     
     
         29 - 46 . (canceled) 
     
     
         47 . A method for reducing or preventing a metabolic disease comprising administering to a human a therapeutically effective amount of a compound of  claim 1 , thereby reducing or preventing a metabolic disease. 
     
     
         48 . The method of  claim 47 , wherein the metabolic disease is obesity. 
     
     
         49 . The method of  claim 47 , comprising co-administering the compound or composition and a second agent. 
     
     
         50 - 91 . (canceled)