US2016257954A1PendingUtilityA1

SERPINC1 iRNA COMPOSITIONS AND METHODS OF USE THEREOF

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Assignee: ALNYLAM PHARMACEUTICALS INCPriority: Apr 26, 2012Filed: Mar 15, 2016Published: Sep 8, 2016
Est. expiryApr 26, 2032(~5.8 yrs left)· nominal 20-yr term from priority
Inventors:Akin AkincAlfica SehgalIvanka ToudjarskaDonald C. FosterStuart MilsteinBrian BettencourtMartin MaierKlaus CharisseSatyanarayana KuchimanchiKallanthottathil G. RajeevMuthiah Manoharan
A61P 43/00A61P 7/04C12N 2310/3515C12N 2310/315C12N 15/113A61K 31/713C12N 2310/322C12N 2310/335C12N 2310/321C12N 2310/3521C12N 2310/14C12N 2310/3533C12N 2320/30C12N 2310/351C12N 2310/3523C12N 2310/3525C07H 21/04A61K 31/7088
59
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Claims

Abstract

The invention relates to iRNA, e.g., double-stranded ribonucleic acid (dsRNA), compositions targeting the Serpinc1 gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of Serpinc1 and methods of treating subjects having a bleeding disorder, such as a hemophilia.

Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . A method of treating a subject having a hemophilia, comprising administering to the subject a therapeutically effective amount of a double stranded ribonucleic acid (dsRNAi) agent,
 wherein the dsRNAi agent comprises a sense strand and an antisense strand,   wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:1 and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:5, thereby treating the subject having a hemophilia.   
     
     
         2 . A method of treating a subject having a hemophilia, comprising administering to the subject a therapeutically effective amount of a double stranded ribonucleic acid (dsRNAi) agent,
 wherein the dsRNAi agent comprises a sense strand and an antisense strand, wherein the antisense strand comprises a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:5, thereby treating the subject having a hemophilia.   
     
     
         3 . A method of preventing at least one symptom in a subject having a hemophilia, comprising administering to the subject a therapeutically effective amount of a double stranded ribonucleic acid (dsRNAi) agent,
 wherein the dsRNAi agent comprises a sense strand and an antisense strand,   wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:1 and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:5, thereby preventing at least one symptom in the subject having a hemophilia.   
     
     
         4 . A method of preventing at least one symptom in a subject having a hemophilia, comprising administering to the subject a therapeutically effective amount of a double stranded ribonucleic acid (dsRNAi) agent,
 wherein the dsRNAi agent comprises a sense strand and an antisense strand, wherein the antisense strand comprises a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:5, thereby preventing at least one symptom in the subject having a hemophilia.   
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strand nucleotide sequences provided in any one of Tables 3, 4, 8, 11, 12, 14, 15, 20, and 21, and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense nucleotide sequences provided in any one of Tables 3, 4, 8, 11, 12, 14, 15, 20, and 21. 
     
     
         6 . The method of any one of  claims 1 - 4 , wherein the nucleotide sequence of the sense strand and the nucleotide sequence of the antisense strand comprise the sense strand nucleotide sequence and the antisense strand nucleotide sequence of a dsRNAi agent selected from the group consisting of AD-50487.1, AD-50477.1, AD-50483.1, AD-50475.1, AD-50495.1, AD-50476.1, AD-50499.1, AD-50478.1, AD-50489.1, AD-50501.1, AD-50507.1, AD-50484.1, AD-50515.1, AD-50540.1, AD-50528.1, AD-50549.1, AD-50539.1, AD-50534.1, AD-50527.1, AD-50514.1, AD-50509.1, AD-50529.1, AD-54944. 
     
     
         7 . The method of  claim 1 , wherein at least one of the nucleotides of the dsRNAi agent is a modified nucleotide. 
     
     
         8 . The method of  claim 7 , wherein the modified nucleotide is selected from the group consisting of a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. 
     
     
         9 . The method of  claim 8 , wherein the modified nucleotide is selected from the group consisting of a 2′-O-methyl (2′-OMe) modified nucleotide and 2′-fluoro modified nucleotide. 
     
     
         10 . The method of  claim 1 , wherein the antisense strand further comprises at least one phosphorothioate internucleoside linkage. 
     
     
         11 . The method of  claim 1 , wherein the antisense strand further comprises at least two phosphorothioate internucleoside linkages. 
     
     
         12 . The method of  claim 1 , wherein the antisense strand further comprises at least three phosphorothioate internucleoside linkages. 
     
     
         13 . The method of  claim 1 , wherein the antisense strand further comprises at least four phosphorothioate internucleoside linkages. 
     
     
         14 . The method of any one of  claims 1 - 4 , wherein the sense strand further comprises at least one phosphorothioate internucleoside linkage. 
     
     
         15 . The method of  claim 1 , wherein the sense strand further comprises at least two phosphorothioate internucleoside linkages. 
     
     
         16 . The method of  claim 1 , wherein the antisense strand further comprises a 3′ overhang of at least 1 nucleotide. 
     
     
         17 . The method of  claim 1 , wherein the antisense strand further comprises a 3′ overhang of at least 2 nucleotides. 
     
     
         18 . The method of  claim 1 , wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides. 
     
     
         19 . The method of  claim 2 , wherein the region of complementarity is at least 17 nucleotides in length. 
     
     
         20 . The method of  claim 2 , wherein the region of complementarity is between 19 and 21 nucleotides in length. 
     
     
         21 . The method of  claim 20 , wherein the region of complementarity is 19 nucleotides in length. 
     
     
         22 . The method of  claim 1 , wherein each strand is no more than 30 nucleotides in length. 
     
     
         23 . The method of  claim 1 , wherein the dsRNAi agent further comprises a ligand. 
     
     
         24 . The method of  claim 23 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNAi agent. 
     
     
         25 . The method of  claim 23 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         26 . The method of  claim 23 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of  claim 23 , wherein the dsRNAi agent is conjugated to the ligand as shown in the following schematic 
       
         
           
           
               
               
           
         
         and, wherein X is O or S. 
       
     
     
         28 . The method of  claim 27 , wherein the X is O. 
     
     
         29 . The method of  claim 2  or  4 , wherein the region of complementarity comprises the nucleotide sequence of 5′-UUGAAGUAAAUGGUGUUAACCAG-3′ (SEQ ID N0:562) 
     
     
         30 . The method of any one of  claims 1 - 4 , wherein the sense strand comprises the nucleotide sequence of 5′-GGUUAACACCAUUUACUUCAA-3′ (SEQ ID NO:294), and the antisense strand comprises the nucleotide sequence of 5′-UUGAAGUAAAUGGUGUUAACCAG-3′ (SEQ ID NO:562). 
     
     
         31 . The method of  claim 30 , wherein the sense strand comprises 5′-GfgUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID N0:956) and the antisense strand comprises 5′-uUfgAfaGfuAfaAfuggUfgUfuAfaCfcsAfsg-3′ (SEQ ID NO:975),
 wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, and U; and s is a phosphorothioate linkage. 
 
     
     
         32 . The method of  claim 30 , wherein the sense strand comprises 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:941) and the antisense strand comprises 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:960),
 wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, and U; and s is a phosphorothioate linkage. 
 
     
     
         33 . The method of  claim 1 , wherein the Serpinc1 expression in the subject is inhibited by at least about 30%. 
     
     
         34 . The method of  claim 1 , wherein the administration of the dsRNAi agent to the subject causes an increase in blood clotting and/or a decrease in Serpinc1 protein accumulation. 
     
     
         35 . The method of  claim 1 , wherein the subject is a human. 
     
     
         36 . The method of  claim 1 , wherein the hemophilia is hemophilia A. 
     
     
         37 . The method of  claim 1 , wherein the hemophilia is hemophilia B. 
     
     
         38 . The method of  claim 1 , wherein the hemophilia is hemophilia C. 
     
     
         39 . The method of  claim 1 , wherein the hemophilia is hemophilia A and the subject is an inhibitor subject. 
     
     
         40 . The method of  claim 1 , wherein the hemophilia is hemophilia B and the subject is an inhibitor subject. 
     
     
         41 . The method of  claim 1 , wherein the hemophilia is hemophilia C and the subject is an inhibitor subject. 
     
     
         42 . The method of  claim 1 , wherein the dsRNAi agent is administered to the subject at a dose of about 10 mg/kg to about 30 mg/kg. 
     
     
         43 . The method of  claim 1 , wherein the dsRNAi agent is administered to the subject at a dose selected from the group consisting of 0.3 mg/kg 0.5 mg/kg 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg. 
     
     
         44 . The method of  claim 1 , wherein the dsRNAi agent is administered to the subject once a week. 
     
     
         45 . The method of  claim 1 , wherein the dsRNAi agent is administered to the subject twice a month. 
     
     
         46 . The method of  claim 1 , wherein the dsRNAi agent is administered to the subject subcutaneously at a cumulative weekly dose of about 0.5 mg/kg to about 5 mg/kg. 
     
     
         47 . The method of  claim 1 , further comprising administering to the subject an additional therapeutic treatment. 
     
     
         48 . The method of any one of  claims 1 - 4 , further comprising measuring thrombin levels in the subject.

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