Compounds and methods for modulating tmprss6 expression

Abstract

Disclosed herein are compositions and compounds comprising modified oligonucleotides for modulating TMPRSS6 and modulating an iron accumulation disease, disorder and/or condition in an individual in need thereof. Iron accumulation diseases in an individual such as polycythemia, hemochromatosis or β-thalassemia can be treated, ameliorated, delayed or prevented with the administration of antisense compounds targeted to TMPRSS6.

1 .- 36 . (canceled) 
     
     
         37 . A compound comprising a modified oligonucleotide, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, and wherein at least 12 linked nucleosides of the modified oligonucleotide has a nucleobase sequence selected from SEQ ID NOS: 9-11, 15-19, and 22-24. 
     
     
         38 . The compound of  claim 37 , wherein the modified oligonucleotide has a nucleobase sequence that is at least 85% complementary to SEQ ID NO: 1. 
     
     
         39 . The compound of  claim 37 , wherein the modified oligonucleotide consists of a single stranded modified oligonucleotide. 
     
     
         40 . The compound of  claim 37 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         41 . The compound of  claim 40 , wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         42 . The compound of  claim 37 , wherein the modified oligonucleotide comprises at least one modified sugar. 
     
     
         43 . The compound of  claim 42 , wherein the at least one modified sugar comprises a 2′-O-methoxyethyl group, a 2′-O—CH 3  group, or a combination thereof. 
     
     
         44 . The compound of  claim 42 , wherein the at least one modified sugar is a bicyclic sugar. 
     
     
         45 . The compound of  claim 44 , wherein the bicyclic sugar comprises a 4′-(CH 2 )—O-2′ bridge, a 4′-(CH 2 ) 2 —O-2′ bridge, or a 4′-CH(CH 3 )—O-2′ bridge. 
     
     
         46 . The compound of  claim 37 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment of linked nucleosides; and   a 3′ wing segment of linked nucleosides;   wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         47 . The compound of  claim 46 , 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 immediately adjacent to and 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 the modified oligonucleotide comprises at least one phosphorothioate internucleoside linkage.   
     
     
         48 . The compound of  claim 37 , comprising a conjugate group, wherein the conjugate moiety comprises at least one N-acetyl galactosamine (GalNAc). 
     
     
         49 . The compound of  claim 48 , wherein the conjugate group has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         50 . The compound of  claim 47 , comprising a conjugate group, wherein the conjugate moiety comprises at least one N-acetyl galactosamine (GalNAc). 
     
     
         51 . The compound of  claim 50 , wherein the conjugate group has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         52 . A pharmaceutical composition comprising the compound of  claim 37  and a pharmaceutically acceptable carrier or diluent. 
     
     
         53 . The pharmaceutical composition of  claim 52 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS). 
     
     
         54 . The pharmaceutical composition of  claim 53 , consisting essentially of the compound and PBS. 
     
     
         55 . A method comprising administering the compound of  claim 37  to a subject in need thereof. 
     
     
         56 . The method of  claim 55 , wherein the subject in need thereof has a thalassemia.