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.

What is claimed is: 
     
         1 . A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases complementary to an equal length portion of nucleobases 3162 to 3184 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 1. 
     
     
         2 . The compound of  claim 1 , wherein the modified oligonucleotide consists of 15 to 30, 15 to 25, 15 to 24, 16 to 24, 17 to 24, 18 to 24, 19 to 24, 20 to 24, 19 to 22, 20 to 22, 16 to 20, 16 or 20 linked nucleosides. 
     
     
         3 . The compound of  claim 1 , wherein the modified oligonucleotide comprises a nucleobase sequence comprising a portion of at least 10, least 11, at least 12, least 13, at least 14, least 15, at least 16, least 17, at least 18, at least 19, or at least 20 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 1 
     
     
         4 . The compound of any preceding claim, wherein the nucleobase sequence of the modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 1 
     
     
         5 . A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or 16 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 63, 77. 
     
     
         6 . A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23, 36, 37. 
     
     
         7 . A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 36. 
     
     
         8 . The compound of any preceding claim, wherein the modified oligonucleotide is single-stranded. 
     
     
         9 . The compound of any preceding claim, wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         10 . The compound of  claim 9 , wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         11 . The compound of  claim 9 , wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         12 . The compound of any preceding claim, wherein the modified oligonucleotide comprises at least one modified sugar. 
     
     
         13 . The compound of  claim 12 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         14 . The compound of  claim 12 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a constrained ethyl, a 3′-fluoro-HNA or a 4′- (CH 2 ) n —O-2′ bridge, wherein n is 1 or 2. 
     
     
         15 . The compound of any preceding claim, wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         16 . The compound of  claim 15 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         17 . The compound of any preceding claim, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides and comprises:
 a. a gap segment consisting of linked deoxynucleosides;   b. a 5′ wing segment consisting of linked nucleosides; and   c. 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.   
     
     
         18 . The compound of  claim 17 , wherein the modified oligonucleotide consists of 16 to 20 linked nucleobases. 
     
     
         19 . The compound of  claim 17 , wherein the modified oligonucleotide consists of 20 linked nucleosides comprising:
 a. a gap segment consisting of ten linked deoxynucleosides;   b. a 5′ wing segment consisting of five linked nucleosides; and   c. 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, wherein at least one internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.   
     
     
         20 . A compound comprising a modified oligonucleotide consisting of 20 linked nucleosides having a nucleobase sequence comprising at least 8 contiguous nucleobases of SEQ ID NO: 36, wherein the modified oligonucleotide comprises:
 a. a gap segment consisting of ten linked deoxynucleosides;   b. a 5′ wing segment consisting of five linked nucleosides;   c. a 3′ wing segment consisting of five linked nucleosides; and   d. a GalNAc conjugate;   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, wherein at least one internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.   
     
     
         21 . A compound comprising a modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence comprising at least 8 contiguous nucleobases of SEQ ID NO: 77, wherein the modified oligonucleotide comprises:
 a. a gap segment consisting of nine linked deoxynucleosides;   b. a 5′ wing segment consisting of three linked nucleosides;   c. a 3′ wing segment consisting of four linked nucleosides; and   d. a GalNAc conjugate;   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 modified sugar, wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.   
     
     
         22 . A compound comprising a modified oligonucleotide according to the following formula: mCes Teo Teo Teo Aeo Tds Tds mCds mCds Ads Ads Ads Gds Gds Gds mCeo Aeo Ges mCes Te (SEQ ID NO: 98); wherein,
 A=an adenine,   mC=a 5-methylcytosine   G=a guanine,   T=a thymine,   e=a 2′-O-methoxyethyl modified nucleoside,   d=a 2′-deoxynucleoside, and   s=a phosphorothioate internucleoside linkage.   
     
     
         23 . A compound comprising a modified oligonucleotide according to the following formula: mCks Aes Gks mCds Tds Tds Tds Ads Tds Tds mCds mCds Aes Aes Aks Gk (SEQ ID NO: 96); wherein,
 A=an adenine,   mC=a 5-methylcytosine   G=a guanine,   T=a thymine,   e=a 2′-O-methoxyethyl modified nucleoside,   d=a 2′-deoxynucleoside,   s=a phosphorothioate internucleoside linkage, and   k=a constrained ethyl.   
     
     
         24 . The compound of any preceding claim, further comprising a conjugated GalNAc moiety. 
     
     
         25 . A modified oligonucleotide according to the following formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         26 . A modified oligonucleotide according to the following formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         27 . A composition comprising a compound or modified oligonucleotide of any preceding claim, or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         28 . A composition comprising a compound or modified oligonucleotide of any preceding claim, for use in therapy. 
     
     
         29 . A composition comprising a compound or modified oligonucleotide of any preceding claim, for use in the preparation of a medicament. 
     
     
         30 . The compound or modified oligonucleotide of any preceding claim, for use in reducing TMPRSS6 in a cell, tissue, organ or animal. 
     
     
         31 . The compound or modified oligonucleotide of any preceding claim, for use in reducing iron accumulation, increasing hepcidin expression levels, and/or decreasing the percentage saturation of transferrin in an animal. 
     
     
         32 . The compound or modified oligonucleotide of any preceding claim, for use in treating, preventing, or slowing progression of a disease, disorder or condition related to excess iron accumulation in an animal. 
     
     
         33 . The compound or modified oligonucleotide of  claim 32 , wherein the disease, disorder or condition is polycythemia, hemochromatosis or anemia. 
     
     
         34 . The compound or modified oligonucleotide of  claim 33 , wherein the anemia is hereditary anemia, myelodysplastic syndrome or severe chronic hemolysis. 
     
     
         35 . The compound or modified oligonucleotide  claim 34 , wherein the hereditary anemia is sickle cell anemia, thalassemia, Fanconi anemia, Diamond Blackfan anemia, Shwachman Diamond syndrome, red cell membrane disorders, glucose-6-phosphate dehydrogenase deficiency, or hereditary hemorrhagic telangiectasia. 
     
     
         36 . The compound or modified oligonucleotide  claim 35 , wherein the thalassemia is β-thalassemia.