Compositions and methods for inhibiting expression of the lect2 gene

Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the LECT2 gene, and methods of using such dsRNA compositions to alter (e.g., inhibit) expression of LECT2.

1 . (canceled) 
     
     
         2 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of LECT2, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a LECT2 RNA transcript, which antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences listed in Tables 2-3, 5-6 and 9-10. 
     
     
         3 . The dsRNA of  claim 2 , wherein said dsRNA comprises at least one modified nucleotide. 
     
     
         4 .- 9 . (canceled) 
     
     
         10 . The dsRNA of  claim 2 , wherein the duplex region is 15-30, 17-23, 19-21, or 21-23 nucleotide pairs in length. 
     
     
         11 .- 13 . (canceled) 
     
     
         14 . The dsRNA of  claim 2 , wherein the region of complementarity is at least 17 nucleotides in length. 
     
     
         15 . (canceled) 
     
     
         16 . The dsRNA of  claim 2 , wherein the region of complementarity is between 19, 20, or 21 nucleotides in length. 
     
     
         17 . The dsRNA of  claim 2 , wherein at least one strand comprises a 3′ overhang of at least 1 or 2 nucleotide. 
     
     
         18 . (canceled) 
     
     
         19 . The dsRNA of  claim 3 , wherein the at least one of said modified nucleotide is chosen from a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, or both. 
     
     
         20 . The dsRNA of  claim 19 , wherein the dsRNA comprises one or more phosphorothioate linkages. 
     
     
         21 . The dsRNA of  claim 3 , wherein the dsRNAcomprises modifications over the entire length of the sense and antisense strands. 
     
     
         22 . (canceled) 
     
     
         23 . The dsRNA of  claim 2  wherein the sense strand is conjugated to at least one ligand. 
     
     
         24 . The dsRNA of  claim 23 , wherein the ligand is attached to the 3′ end of the sense strand. 
     
     
         25 . (canceled) 
     
     
         26 . The dsRNA of  claim 23 , wherein the ligand is a GalNAc ligand. 
     
     
         27 . The dsRNA of  claim 23 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         28 .- 29 . (canceled) 
     
     
         30 . The dsRNA of  claim 23 , wherein the ligand is attached via a linker, and the ligand and linker are as shown in Formula XXIV: 
       
         
           
           
               
               
           
         
       
     
     
         31 . (canceled) 
     
     
         32 . The dsRNA of  claim 2 , wherein the region of complementarity consists of an antisense sequence selected from the antisense sequences disclosed in Tables 2-3, 5-6 and 9-10. 
     
     
         33 . The dsRNA of  claim 2 , wherein the dsRNA comprises a sense strand consisting of a sense sequence selected from the sense sequences disclosed in Tables 2-3, 5-6 and 9-10, and an antisense strand consisting of an antisense sequence selected from the antisense sequences disclosed in Tables 2-3, 5-6 and 9-10. 
     
     
         34 . A cell containing the dsRNA of  claim 2 . 
     
     
         35 . A pharmaceutical composition for inhibiting expression of a LECT2 gene, the composition comprising the dsRNA of  claim 2 . 
     
     
         36 .- 40 . (canceled) 
     
     
         41 . The pharmaceutical composition of  claim 35 , wherein said composition comprises a lipid formulation. 
     
     
         42 . (canceled) 
     
     
         43 . The pharmaceutical composition of  claim 41 , wherein the lipid formulation is a LNP11 formulation. 
     
     
         44 .- 48 . (canceled) 
     
     
         49 . A method of inhibiting LECT2 expression in a cell, the method comprising:
 (a) introducing into the cell the dsRNA of  claim 2 , and   (b) maintaining the cell of step (a) for a time sufficient to obtain degradation of the mRNA transcript of a LECT2 gene, thereby inhibiting expression of the LECT2 gene in the cell.   
     
     
         50 . The method of  claim 49 , wherein the cell is treated ex vivo, in vitro, or in vivo. 
     
     
         51 .- 53 . (canceled) 
     
     
         54 . The method of  claim 49 , wherein the cell is a liver cell or a hepatocyte. 
     
     
         55 . (canceled) 
     
     
         56 . The method of  claim 49 , wherein the expression of LECT2 is inhibited by at least 30%. 
     
     
         57 . (canceled) 
     
     
         58 . A method of treating a LECT2 amyloidosis comprising administering to a subject in need of such treatment a double-stranded ribonucleic acid (dsRNA), wherein said dsRNA comprises a sense strand that is 15-30 base pairs in length and an antisense strand that is 15-30 base pairs in length and the antisense strand is complementary to at least 15 contiguous nucleotides of SEQ ID NO: 1 or a nucleotide sequence having an A to G substitution at nucleotide position 373 of SEQ ID NO: 1. 
     
     
         59 .- 61 . (canceled) 
     
     
         62 . The method of  claim 58 , wherein the dosing regimen is weekly, biweekly, or monthly. 
     
     
         63 .- 64 . (canceled) 
     
     
         65 . The method of  claim 58 , wherein the dsRNA is administered at a dose of 0.05-50, 0.01-5, 0.1-0.5, or 1-10 mg/kg body weight of the subject. 
     
     
         66 .- 67 . (canceled) 
     
     
         68 . The method of  claim 65 , wherein the dsRNA is conjugated to a GalNAc ligand. 
     
     
         69 .- 74 . (canceled) 
     
     
         75 . The method of  claim 58 , wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences listed in Tables 2-3, 5-6 and 9-10.