Compounds and methods for modulating expression of gcgr

Abstract

The present disclosure describes short antisense compounds, including such compounds comprising chemically-modified high-affinity monomers 8-16 monomers in length. Certain such short antisense compound are useful for the reduction of target nucleic acids and/or proteins in cells, tissues, and animals with increased potency and improved therapeutic index. Thus, provided herein are short antisense compounds comprising high-affinity nucleotide modifications useful for reducing a target RNA in vivo. Such short antisense compounds are effective at lower doses than previously described antisense compounds, allowing for a reduction in toxicity and cost of treatment. In addition, the described short antisense compounds have greater potential for oral dosing.

1 . A method of treating a metabolic disorder in an animal, comprising administering to an animal a short antisense compound 10 to 14 monomers in length, said compound comprising a 2′-deoxyribonucleotide gap region flanked on each side by a wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers and wherein the compound is targeted to a nucleic acid encoding GCGR. 
     
     
         2 . The method of  claim 1 , wherein administering the antisense compound increases insulin sensitivity, decreases blood glucose and/or decreases HbA 1c  in the animal. 
     
     
         3 . The method of  claim 1 , wherein the gap region is 5, 6, 7, 8, 9, or 10 nucleotides in length. 
     
     
         4 . The method of  claim 1 , wherein said high-affinity modified monomers are sugar-modified nucleotides. 
     
     
         5 . The method of  claim 4 , wherein at least one of the sugar-modified nucleotides comprises a bridge between the 4′ and the 2′ position of the sugar. 
     
     
         6 . The method of  claim 4 , wherein each of said sugar-modified nucleotides comprises a 2′-substituent group that is other than H or OH. 
     
     
         7 . The method of  claim 6 , wherein at least one of said sugar-modified nucleotides is a 4′ to 2′ bridged bicyclic nucleotide. 
     
     
         8 . The method of  claim 6 , wherein each of the 2′-substituent groups is, independently, alkoxy, substituted alkoxy, or halogen. 
     
     
         9 . The method of  claim 8 , wherein each of the 2′-substituent groups is OCH 2 CH 2 OCH 3 . 
     
     
         10 . The method of  claim 5 , wherein the conformation of each of said sugar-modified nucleotides is, independently, β-D or α-L. 
     
     
         11 . The method of  claim 1 , wherein each of the high-affinity modified monomers is independently selected from bicyclic nucleotides or other 2′-modified nucleotides. 
     
     
         12 . The method of  claim 11 , wherein the 2′-modified nucleotides are selected from halogen, allyl, amino, azido, thio, O-allyl, O—C 1 -C 10  alkyl, —OCF 3 , O—(CH 2 ) 2 —O—CH 3 , 2′-O(CH 2 ) 2 SCH 3 , O—(CH 2 ) 2 —O—N(R m )(R n ) or O—CH 2 —C(═O)—N(R m )(R n ), where each R m  and R n  is, independently, H or substituted or unsubstituted C 1 -C 10  alkyl. 
     
     
         13 . The method of  claim 12 , wherein the 2′-modified nucleotide is a 2′-OCH 2 CH 2 OCH 3  nucleotide. 
     
     
         14 . The method of  claim 1 , wherein at least one monomeric linkage is a modified monomeric linkage. 
     
     
         15 . The method of  claim 14 , wherein the modified monomeric linkage is a phosphorothioate linkage. 
     
     
         16 . A method of modulating expression of GCGR by contacting a GCGR nucleic acid with a short antisense compound 10 to 14 monomers in length, said compound comprising a 2′-deoxyribonucleotide gap region flanked on each side by a wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers and wherein the compound is targeted to a nucleic acid encoding GCGR. 
     
     
         17 . The method of  claim 16 , wherein the GCGR nucleic acid is in an animal. 
     
     
         18 . The method of  claim 17 , wherein administering the antisense compound increases insulin sensitivity, decreases blood glucose and/or decreases HbA 1c  in the animal. 
     
     
         19 . A method of inhibiting expression of GCGR RNA in an animal, comprising administering to said animal a short antisense compound 10 to 14 monomers in length, said compound comprising a 2′-deoxyribonucleotide gap region flanked on each side by a wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers and wherein the compound is targeted to a nucleic acid encoding GCGR. 
     
     
         20 . The method of  claim 19 , wherein administering the antisense compound increases insulin sensitivity, decreases blood glucose and/or decreases HbA 1c  in the animal.