Compositions and methods for inhibiting expression of the lect2 gene

Abstract

The invention relates to antisense polynucleotide agents targeting the LECT2 gene, and methods of using such antisense polynucleotide agents to inhibit expression of LECT2 and to treat subjects having a LECT2-associated disease, e.g., amyloidosis.

1 . An antisense polynucleotide agent for inhibiting expression of LECT2, wherein the agent comprises about 4 to about 50 contiguous nucleotides, wherein at least one of the contiguous nucleotides is a modified nucleotide, and wherein the nucleotide sequence of the agent is about 80% complementary over its entire length to the equivalent region of the nucleotide sequence of any one of SEQ ID NOs:1-4, optionally wherein substantially all, or all, of the nucleotides of the antisense polynucleotide agent are modified nucleotides. 
     
     
         2 . (canceled) 
     
     
         3 . An antisense polynucleotide agent for inhibiting expression of LECT2, wherein the agent comprises at least 8 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences listed in Table 3. 
     
     
         4 .- 5 . (canceled) 
     
     
         6 . The agent of  claim 1 , which is 10 to 40 nucleotides in length, 10 to 30 nucleotides in length, 18 to 30 nucleotides in length, 10 to 24 nucleotides in length, 18 to 24 nucleotides in length, or 14 or 20 nucleotides in length. 
     
     
         7 .- 11 . (canceled) 
     
     
         12 . The agent of  claim 1 , wherein the modified nucleotide:
 comprises a modified sugar moiety selected from the group consisting of: a 2′-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, and a bicyclic sugar moiety;   is a 5-methylcytosine; or   comprises a modified internucleoside linkage.   
     
     
         13 .- 16 . (canceled) 
     
     
         17 . The agent of  claim 1 , comprising a plurality of 2′-deoxynucleotides flanked on each side by at least one nucleotide having a modified sugar moiety,
 wherein the agent is a gapmer comprising a gap segment comprised of linked 2′-deoxynucleotides positioned between a 5′ and a 3′ wing segment; or 
 wherein the modified sugar moiety is selected from the group consisting of a 2′-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, and a bicyclic sugar moiety. 
 
     
     
         18 .- 19 . (canceled) 
     
     
         20 . The agent of  claim 17 , wherein:
 the 5′-wing segment is 1 to 6, or 2, 3, 4, or 5 nucleotides in length;   the 3′-wing segment is 1 to 6, or 2, 3, 4, or 5 nucleotides in length; and/or   the gap segment is 5 to 14, or 10 nucleotides in length.   
     
     
         21 .- 31 . (canceled) 
     
     
         32 . An antisense polynucleotide agent for inhibiting LECT2 expression, comprising:
 a gap segment consisting of linked deoxynucleotides;   a 5′-wing segment consisting of linked nucleotides;   a 3′-wing segment consisting of linked nucleotides;   wherein the gap segment is positioned between the 5′-wing segment and the 3′-wing segment and wherein each nucleotide of each wing segment comprises a modified sugar.   
     
     
         33 . The agent of  claim 32 , wherein the gap segment is ten 2′-deoxynucleotides in length and each of the wing segments is two, three, four, or five nucleotides in length; or wherein the modified sugar moiety is selected from the group consisting of a 2′-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, and a bicyclic sugar moiety. 
     
     
         34 .- 37 . (canceled) 
     
     
         38 . The agent of  claim 1 , wherein the agent further comprises a ligand. 
     
     
         39 . The agent of  claim 38 , wherein the antisense polynucleotide agent is conjugated to the ligand at the 3′-terminus, optionally wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         40 . (canceled) 
     
     
         41 . The agent of  claim 39 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         42 . A pharmaceutical composition for inhibiting expression of a LECT2 gene comprising the agent of  claim 1 . 
     
     
         43 .- 47 . (canceled) 
     
     
         48 . A pharmaceutical composition comprising the agent of  claim 1 , and a lipid formulation, wherein the lipid formulation comprises an LNP or an MC3. 
     
     
         49 .- 50 . (canceled) 
     
     
         51 . A method of inhibiting LECT2 expression in a cell, the method comprising:
 (a) contacting the cell with the agent of  claim 1 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain antisense inhibition of a LECT2 gene, thereby inhibiting expression of the LECT2 gene in the cell.   
     
     
         52 .- 54 . (canceled) 
     
     
         55 . A method of treating a subject having a disease or disorder that would benefit from reduction in LECT2 expression, the method comprising administering to the subject a therapeutically effective amount of the agent of  claim 1 , thereby treating the subject. 
     
     
         56 . A method of preventing at least one symptom in a subject having a disease or disorder that would benefit from reduction in LECT2 expression, the method comprising administering to the subject a prophylactically effective amount of the agent of  claim 1 , thereby preventing at least one symptom in the subject having a disorder that would benefit from reduction in LECT2 expression. 
     
     
         57 . (canceled) 
     
     
         58 . The method of  claim 55 , wherein the disorder is a LECT2-associated disease, and wherein the LECT2-associated disease is selected from the group consisting of an amyloidosis, an elevated risk for developing amyloidosis, a rheumatoid arthritis, and an acute liver injury. 
     
     
         59 .- 60 . (canceled) 
     
     
         62 . (canceled) 
     
     
         63 . The method of  claim 55 , further comprising administering a second therapy to the subject, wherein the second therapy is a therapy that supports kidney function such as dialysis, a diuretic, an angiotensin converting enzyme (ACE) inhibitor, and an angiotensin receptor blocker (ARB); a therapy that supports liver function; or removal of all or part of the organs affected by the amyloidosis. 
     
     
         64 .- 66 . (canceled) 
     
     
         67 . The method  claim 55 , wherein the agent is administered at a dose of about 0.01 mg/kg to about 100 mg/kg, such as at a dose of about 0.5 mg/kg to about 10 mg/kg; and/or is administered to the subject once a week, twice a week, or twice a month. 
     
     
         68 .- 71 . (canceled) 
     
     
         72 . The method of  claim 55 , wherein the agent is administered to the subject subcutaneously.