Methods and compositions for treating a serpinc1-associated disorder

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 to treat subjects having a Serpinc1-associated disease, e.g., a bleeding disorder, such as a hemophilia.

1 . A method of preventing at least one symptom in a subject having a disorder that would benefit from reduction in SERPINC1 expression, comprising administering to the subject a dose of about 25 mg to about 100 mg of a double stranded ribonucleic acid (dsRNA) molecule,
 wherein the dsRNA molecule comprises a sense strand and an antisense strand, the antisense strand comprising at least 15 contiguous nucleotides differing by no more than three nucleotides from the nucleotide sequence 5′-UUGAAGUAAAUGGUGUUAACCAG-3′ (SEQ ID NO: 15), wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, and wherein the sense strand is conjugated to a ligand attached at the 3′ end.   
     
     
         2 - 41 . (canceled) 
     
     
         42 . A kit comprising
 a) a dose of about 25 mg to about 100 mg of a double stranded ribonucleic acid (dsRNA) molecule comprising a sense strand and an antisense strand,   wherein the sense strand comprises the sequence 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:13) and the antisense strand comprises the sequence 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:14), wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively: Af, Cf, Gf and Uf are 2′-fluoro A, C, G, and U, respectively; and s is a phosphorothioate linkage; and   wherein a ligand is conjugated to the 3′ end of the sense strand as shown in the following schematic;   
       
         
           
           
               
               
           
         
       
       wherein X is O,
 b) instructions for use, and 
 c) optionally, means for administering the dsRNA molecule to a subject. 
 
     
     
         43 . The kit of  claim 42 , wherein the sequence of the sense strand consists of SEQ ID NO:13 and the sequence of the antisense strand consists of SEQ ID NO:14. 
     
     
         44 . The kit of  claim 42 , wherein the dsRNA molecule is formulated in a phosphate-buffered saline. 
     
     
         45 . The kit of  claim 42 , wherein the dose of the dsRNA molecule is 50 mg. 
     
     
         46 . The kit of  claim 42 , wherein the dose of the dsRNA molecule is 80 mg. 
     
     
         47 . The kit of  claim 42 , wherein the kit comprises more than one dose of the dsRNA molecule. 
     
     
         48 . The kit of  claim 42 , wherein the means for administration is an injection device for subcutaneous administration. 
     
     
         49 . The kit of  claim 42 , wherein the kit is for treating a disorder that would benefit from reduction in SERPINC1 expression in the subject. 
     
     
         50 . The kit of  claim 42 , wherein the kit is for treating a human subject with hemophilia A or hemophilia B. 
     
     
         51 . The kit of  claim 50 , wherein the subject is a hemophilia A patient with inhibitors or a hemophilia B patient with inhibitors. 
     
     
         52 . The kit of  claim 50 , wherein the subject is a hemophilia A patient without inhibitors or a hemophilia B patient without inhibitors. 
     
     
         53 . The kit of  claim 50 , wherein the kit is for reducing the annual bleed rate (ABR) in the subject. 
     
     
         54 . The kit of  claim 53 , wherein administration of the dsRNA molecule to the subject reduces ABR of the subject to one or less. 
     
     
         55 . The kit of  claim 50 , wherein the kit is for reducing the annual spontaneous bleeding rate (AsBR) in the subject. 
     
     
         56 . The kit of  claim 55 , wherein administration of the dsRNA molecule to the subject reduces AsBR of the subject to zero.