Compounds and methods for improving cellular uptake of oligomeric compounds

Abstract

The present invention provides method of optimizing the efficacy and potency of antisense drugs. In certain embodiments, the invention provides assays useful for determining favorable oligonucleotide characteristics and excipeints for improved cellular uptake.

1 .- 20 . (canceled) 
     
     
         21 . A formulation comprising an antisense oligomeric compound and an excipient, wherein the excipient increases cellular uptake of the oligomeric compound. 
     
     
         22 . The formulation of  claim 21  wherein the excipient preferentially binds to a non-productive mechanism of cellular accumulation. 
     
     
         23 .- 26 . (canceled) 
     
     
         27 . The method of  claim 21 , wherein the oligomeric compound is a modified oligonucleotide. 
     
     
         28 . The method of  claim 27 , wherein the oligomeric compound consists of 17 linked nucleosides. 
     
     
         29 . The method of  claim 27 , wherein the oligomeric compound consists of 18 linked nucleosides. 
     
     
         30 . The method of  claim 27 , wherein the oligomeric compound consists of 19 linked nucleosides. 
     
     
         31 . The method of  claim 27 , wherein the oligomeric compound consists of 20 linked nucleosides. 
     
     
         32 . The method of  claim 27 , wherein the oligomeric compound consists of 21 linked nucleosides. 
     
     
         33 . The method of  claim 27 , wherein the oligomeric compound comprises a nucleoside comprising a 2′ modification. 
     
     
         34 . The method of  claim 33 , wherein the 2′-modification is selected from among: allyl, amino, azido, thio, O-allyl, O—C 1 -C 10  alkyl, —OCF 3 , O—(CH 2 ) 2 -O—CH 3 , 2′-O(CH 2 ) 2 SCH 3 , O—(CH 2 ) 2 —O—N(R m )(R n ), or O—CH 2 —C(═O)—N(R m )(R n ), where each R m  and R n  is, independently, H or substituted or unsubstituted C 1 -C 10  alkyl. 
     
     
         35 . The method of  claim 33 , wherein the 2′-modification is 2′-O—(CH 2 ) 2 —O—CH 3 . 
     
     
         36 . The method of  claim 33 , wherein the 2′-modification is 2′-OCH 3 . 
     
     
         37 . The method of  claim 27 , wherein the oligomeric compound comprises a bicyclic nucleic acid. 
     
     
         38 . The method of  claim 27 , wherein the oligomeric compound is a gapmer. 
     
     
         39 . The method of  claim 38 , wherein the oligomeric compound is a 2-8-3 MOE-DNA gapmer. 
     
     
         40 . The method of  claim 27 , wherein the oligomeric compound is fully modified. 
     
     
         41 . The method of  claim 21 , wherein the excipient is not a cationic lipid. 
     
     
         42 . The method of  claim 41 , wherein the excipient is dextran. 
     
     
         43 . The method of  claim 41 , wherein the excipient is dextran sulfate. 
     
     
         44 . The method of  claim 27 , wherein the oligomeric compound comprises at least 1 phosphorothioate internucleoside linkage.