SERUM AMYLOID P COMPONENT (APCS) iRNA COMPOSITIONS AND METHODS OF USE THEREOF

Abstract

The invention relates to iRNA, e.g., double stranded ribonucleic acid (dsRNA), compositions targeting the serum amyloid P component (APCS) gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of an APCS gene and to treat subjects having an APCS-associated disease, e.g., amyloidosis, Alzheimer's disease or coronary atherosclerotic heart disease.

1 . A double stranded ribonucleic acid (RNAi) agent for inhibiting expression of a serum amyloid P component (APCS) gene, comprising 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. 
     
     
         2 . A double stranded ribonucleic acid (RNAi) agent for inhibiting expression of a serum amyloid P component (APCS) gene, comprising a sense strand and an antisense strand, wherein the antisense strand comprises a region of complementarity comprising at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense sequences listed in any one of Tables 3A, 3B, 4A, 4B, 6, and 7. 
     
     
         3 . A double stranded ribonucleic acid (RNAi) agent for inhibiting expression of a serum amyloid P component (APCS) gene, comprising a sense strand and an antisense strand, wherein said antisense strand comprises a region complementary to part of an mRNA encoding SAP, wherein each strand is about 14 to about 30 nucleotides in length, wherein said sense strand is represented by formula (I):
   sense: 5′n p -N a -(X X X) i -N b -Y Y Y -N b -(Z Z Z) j -N a -n q  3′  (I)
   wherein:   i and j are each independently 0 or 1;   p and q are each independently 0-6;   N a  represents an oligonucleotide sequence comprising 0-25 nucleotides which are either modified or unmodified or combinations thereof;   N b  represents an oligonucleotide sequence comprising 0-10 nucleotides which are either modified or unmodified or combinations thereof;   each n p  and n q , each of which may or may not be present, independently represents an overhang nucleotide;   XXX, YYY and ZZZ each independently represent one motif of three identical modifications on three consecutive nucleotides;   modifications on N b  differ from the modification on Y; and   wherein the sense strand is conjugated to at least one ligand.   
     
     
         4 .- 10 . (canceled) 
     
     
         11 . The double stranded RNAi agent of  claim 1 , wherein the sense and antisense strands comprise nucleotide sequences selected from any of the nucleotide sequences in any one of Tables 3A, 3B, 4A, 4B, 6, and 7. 
     
     
         12 . (canceled) 
     
     
         13 . The double stranded RNAi agent of  claim 1 , wherein said RNAi agent comprises at least one modified nucleotide. 
     
     
         14 .- 17 . (canceled) 
     
     
         18 . The double stranded RNAi agent of  claim 13 , further comprising at least one phosphorothioate internucleotide linkage. 
     
     
         19 . The double stranded RNAi agent of  claim 1 , wherein the region of complementarity between said sense strand and said antisense strand is at least 17 nucleotides in length; 19 to 30 nucleotides in length; 21 nucleotides in length; 21 to 23 nucleotides in length; or 19 nucleotides in length. 
     
     
         20 .- 23 . (canceled) 
     
     
         24 . The double stranded RNAi agent of  claim 1 , wherein each strand is no more than 30 nucleotides in length; each strand is independently 19-30 nucleotides in length; or each strand is independently 19-25 nucleotides in length. 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . The double stranded RNAi agent of  claim 24 , wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length. 
     
     
         28 . The double stranded RNAi agent of  claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or a 3′ overhang of at least 2 nucleotides. 
     
     
         29 . (canceled) 
     
     
         30 . The double stranded RNAi agent of  claim 1 , further comprising a ligand. 
     
     
         31 . (canceled) 
     
     
         32 . The double stranded RNAi agent of  claim 30 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         33 . The double stranded RNAi agent of  claim 32 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         34 . The double stranded RNAi agent of  claim 33 , wherein the double stranded RNAi agent is conjugated to the ligand as shown in the following schematic 
       
         
           
           
               
               
           
         
         and wherein X is O or S. 
       
     
     
         35 . The double stranded RNAi agent of  claim 34 , wherein the X is O. 
     
     
         36 . (canceled) 
     
     
         37 . A cell containing the double stranded RNAi agent of  claim 1 . 
     
     
         38 . (canceled) 
     
     
         39 . A pharmaceutical composition for inhibiting expression of a serum amyloid P component (APCS) gene comprising the double stranded RNAi agent of  claim 1 . 
     
     
         40 .- 44 . (canceled) 
     
     
         45 . A method of inhibiting expression of a serum amyloid P component (APCS) gene in a cell, the method comprising contacting the cell with the double stranded RNAi agent of  claim 1 , thereby inhibiting expression of the APCS gene in the cell. 
     
     
         46 .- 50 . (canceled) 
     
     
         51 . A method of treating a subject having a disease that would benefit from reduction in serum amyloid P component (APCS) gene expression, comprising administering to the subject a therapeutically effective amount of the double stranded RNAi agent of  claim 1 , thereby treating said subject. 
     
     
         52 .- 62 . (canceled) 
     
     
         63 . A method of inhibiting the expression of an APCS protein (SAP) in a subject, the method comprising
 administering to said subject a therapeutically effective amount of the double stranded RNAi agent of  claim 1 , thereby inhibiting the expression of APCS in said subject.