Beta catenin nucleic acid inhibitor molecule

Abstract

Provided herein is a potent, optimized β-catenin nucleic acid inhibitor molecule with a unique pattern of modified nucleotides. Also provided are methods and compositions for reducing β-catenin expression and methods and compositions for treating cancer.

1 .- 20 . (canceled) 
     
     
         21 . A method of treating a 0-catenin-associated disorder in a subject, comprising administering to the subject a therapeutically effective amount of a nucleic acid inhibitor molecule in combination with one or more immunotherapeutic agents, wherein the f3-catenin-associated disorder is cancer, wherein the nucleic acid inhibitor molecule comprising a sense strand and an antisense strand and a region of complementarity between the sense strand and the antisense strand of 26 nucleotides,
 wherein the sense strand comprises the nucleic acid of SEQ ID NO: 11; and   wherein the antisense strand comprises the nucleic acid of SEQ ID NO: 12 and includes 2 single-stranded nucleotides at its 3′ terminus and 10 single-stranded nucleotides at its 5′ terminus.   
     
     
         22 . The method of  claim 21 , wherein the administering comprises intravenous, intramuscular, or subcutaneous administration. 
     
     
         23 . The method of  claim 21 , wherein the subject is a human. 
     
     
         24 . The method of  claim 21 , wherein the cancer is colorectal cancer, hepatocellular carcinoma, or melanoma. 
     
     
         25 . The method of  claim 21 , wherein the cancer is immunotherapy resistant. 
     
     
         26 . The method of  claim 21 , wherein the immunotherapeutic agent is an antagonist of an inhibitory immune checkpoint molecule or an agonist of a co-stimulatory checkpoint molecule. 
     
     
         27 . The method of  claim 26 , wherein the immunotherapeutic agent is an IDO inhibitor, an anti-CTLA-4 monoclonal antibody, an anti-PD-1 monoclonal antibody, an anti-PD-L1 monoclonal antibody, or a combination of an anti-CTLA-4 monoclonal antibody and an anti-PD-1 monoclonal antibody. 
     
     
         28 . The method of  claim 26 , wherein the immunotherapeutic agent is an IDO inhibitor. 
     
     
         29 . The method of  claim 26 , wherein the immunotherapeutic agent is an anti-PD-1 monoclonal antibody. 
     
     
         30 . The method of  claim 26 , wherein the immunotherapeutic agent is a combination of an IDO inhibitor and an anti-PD-1 monoclonal antibody. 
     
     
         31 . The method of  claim 21 , wherein the sense strand consists of the nucleic acid of SEQ ID NO: 11. 
     
     
         32 . The method of  claim 21 , wherein the antisense strand consists of the nucleic acid of SEQ ID NO: 12. 
     
     
         33 . The method of  claim 21 , wherein the sense strand consists of the nucleic acid of SEQ ID NO: 11 and the antisense strand consists of the nucleic acid of SEQ ID NO: 12. 
     
     
         34 . The method of  claim 21 , wherein the nucleic acid inhibitor molecule further comprising a 5′-phosphate mimic at the 5′ terminus of the sense strand and/or the antisense strand. 
     
     
         35 . The method of  claim 21 , wherein the nucleic acid inhibitor molecule is formulated with a nanoparticle. 
     
     
         36 . The method of  claim 35 , wherein the lipid nanoparticle comprises core lipids and envelope lipids, wherein the core lipids comprise a first cationic lipid and a first pegylated lipid and wherein the envelope lipids comprise a second cationic lipid, a neutral lipid, a sterol, and a second pegylated lipid. 
     
     
         37 . The method of  claim 36 , wherein the first cationic lipid is DL-048, the first pegylated lipid is DSG-MPEG, the second cationic lipid is DL-103, the neutral lipid is DSPC, the sterol is cholesterol, and the second pegylated lipid is DSPE-MPEG. 
     
     
         38 . A method of treating a 0-catenin-associated cancer in a subject, comprising administering to the subject a therapeutically effective amount of a nucleic acid inhibitor molecule in combination with an IDO inhibitor and an anti-PD-1 monoclonal antibody; wherein the nucleic acid inhibitor molecule comprising a sense strand and an antisense strand and a region of complementarity between the sense strand and the antisense strand of 26 nucleotides,
 wherein the sense strand comprises the nucleic acid of SEQ ID NO: 11; and   wherein the antisense strand comprises the nucleic acid of SEQ ID NO: 12 and includes 2 single-stranded nucleotides at its 3′ terminus and 10 single-stranded nucleotides at its 5′ terminus.   
     
     
         39 . The method of  claim 38 , wherein the nucleic acid inhibitor molecule further comprising a 5′-phosphate mimic at the 5′ terminus of the sense strand and/or the antisense strand. 
     
     
         40 . The method of  claim 38 , wherein the nucleic acid inhibitor molecule is formulated with a nanoparticle.