S-antigen transport inhibiting oligonucleotide polymers and methods

Abstract

Various embodiments provide STOPS™ polymers that are S-antigen transport inhibiting oligonucleotide polymers, processes for making them and methods of using them to treat diseases and conditions. In some embodiments the STOPS™ modified oligonucleotides include an at least partially phosphorothioated sequence of alternating A and C units having modifications as described herein. The sequence independent antiviral activity against hepatitis B of embodiments of STOPS™ modified oligonucleotides, as determined by HBsAg Secretion Assay, is greater than that of a reference compound.

What is claimed is: 
     
         1 . A method of treating hepatitis B and/or hepatitis D, comprising administering an effective amount of a modified oligonucleotide or complex thereof to a subject in need thereof, wherein the modified oligonucleotide is represented by the following formula: 
       
         
           
                 
               
                   (SEQ ID NO: 146) 
                 
                   5′mApsln(5m)CpsmApsln(5m)CpsmApsln(5m)CpsmApsln 
                 
                     
                 
                   (5m)CpsmApsln(5m)CpsrApsln(5m)CpsmApsln(5m) 
                 
                     
                 
                   CpsmApsln(5m)CpsrApsln(5m)CpsmApsln(5m)CpsmApsln 
                 
                     
                 
                   (5m)CpsrApsln(5m)CpsmApsln(5m)CpsmApsln(5m) 
                 
                     
                 
                   CpsrApsln(5m)CpsmApsln(5m)CpsmApsln(5m)CpsrApsln 
                 
                     
                 
                   (5m)CpsmApsln(5m)CpsmApsln(5m)C 3′, 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein mA is 2′-O-methyladenosine, ps is phosphorothioate, ln(5m)C is locked 5-methylcytidine, and rA is ribo-adenosine. 
       
     
     
         2 . The method of  claim 1 , wherein the modified oligonucleotide or complex thereof is administered to the subject by a parenteral route. 
     
     
         3 . The method of  claim 2 , wherein the modified oligonucleotide or complex thereof is administered to the subject intravenously. 
     
     
         4 . The method of  claim 2 , wherein the modified oligonucleotide or complex thereof is administered to the subject subcutaneously. 
     
     
         5 . The method of  claim 1 , further comprising administering an effective amount of one or more of a second treatment for hepatitis B to the subject. 
     
     
         6 . The method of  claim 5 , wherein the second treatment for hepatitis B comprises an siRNA oligonucleotide, an anti-sense oligonucleotide, a nucleoside, an interferon, an immunomodulator, a capsid assembly modulator, or a combination thereof. 
     
     
         7 . The method of  claim 6 , wherein the second treatment for hepatitis B comprises an anti-sense oligonucleotide. 
     
     
         8 . The method of  claim 6 , wherein the second treatment for hepatitis B comprises a capsid assembly modulator. 
     
     
         9 . The method of  claim 1 , comprising subcutaneously administering the modified oligonucleotide or complex thereof to a human subject in need thereof, at a dosage lower than otherwise expected based on liver levels observed following otherwise comparable intravenous administration. 
     
     
         10 . The method of  claim 9 , wherein the complex is a chelate complex. 
     
     
         11 . The method of  claim 9 , wherein the complex is a monovalent counterion complex. 
     
     
         12 . The method of  claim 11 , wherein the complex is a lithium, sodium or potassium complex of the modified oligonucleotide. 
     
     
         13 . The method of  claim 1 , wherein the modified oligonucleotide or complex thereof is administered to the subject in the form of a pharmaceutical composition, wherein the pharmaceutical composition comprises the modified oligonucleotide or complex thereof and a pharmaceutically acceptable carrier. 
     
     
         14 . The method of  claim 13 , wherein the pharmaceutical composition is administered to the subject subcutaneously.