Antisense design

Abstract

A novel class of pharmaceuticals which comprises a Locked Nucleic Acid (LNA) which can be used in antisense therapy. These novel oligonucleotides have improved antisense properties. The novel oligonucleotides are composed of at least one LNA selected from beta-D-thio/amino-LNA or alpha-L-oxy/thio/amino-LNA. The oligonucleotides comprising LNA may also include DNA and/or RNA nucleotides.

1 . (canceled) 
     
     
         43 . A gapmer oligomer having 12-18 nucleotide units comprising a central region of at least 6 contiguous DNA nucleotides which is flanked both 5′ and 3′ by locked nucleotides of formula 
       
         
           
           
               
               
           
         
         wherein X is O; (CH 2 )n is a methylene substituted with a C 1-6  alkyl. 
       
     
     
         44 . The gapmer oligomer of  claim 43  wherein (CH 2 )n is a methylene substituted with a methyl group. 
     
     
         45 . The gapmer oligomer of  claim 44  wherein all of the locked nucleotides have the formula: 
       
         
           
           
               
               
           
         
         wherein X is O; (CH 2 )n is a methylene substituted with a methyl group. 
       
     
     
         46 . The gapmer oligomer of  claim 43  wherein at least one of the internucleotide linkages is a phosphorothioate linkage. 
     
     
         47 . The gapmer oligomer of  claim 43  wherein all of the internucleotide linkages are phosphorothioate linkages. 
     
     
         48 . The gapmer oligomer according to  claim 44  wherein all of the internucleotide linkages are phosphorothioate linkages. 
     
     
         49 . The gapmer oligomer according to  claim 45  wherein all of the internucleotide linkages are phosphorothioate linkages. 
     
     
         50 . The gapmer oligomer of  claim 43  wherein in the central region is 8-12 or more DNA nucleotides. 
     
     
         51 . The gapmer oligomer of  claim 48  wherein in the central region is 8-12 or more DNA nucleotides. 
     
     
         52 . The gapmer oligomer of  claim 49  wherein in the central region is 8-12 or more DNA nucleotides. 
     
     
         53 . The gapmer oligomer of  claim 51 , wherein each of the 5′ and 3′ flanks have 2-6 locked nucleotides. 
     
     
         54 . The gapmer oligomer of  claim 52 , wherein each of the 5′ and 3′ flanks have 2-6 locked nucleotides. 
     
     
         55 . The gapmer oligomer of  claim 51 , wherein each of the 5′ and 3′ flanks have 3 or 4 locked nucleotides. 
     
     
         56 . The gapmer oligomer of  claim 52 , wherein each of the 5′ and 3′ flanks have 3 or 4 locked nucleotides. 
     
     
         57 . The gapmer oligomer according to  claim 53  wherein the oligomer is 15, 16 or 17 nucleotides in length. 
     
     
         58 . The gapmer oligomer according to  claim 54  wherein the oligomer is 15, 16 or 17 nucleotides in length. 
     
     
         60 . The gapmer oligomer of  claim 43  wherein all of the nucleotides other than the DNA nucleotides of the central region are locked nucleotides of formula 
       
         
           
           
               
               
           
         
         wherein X is O; (CH 2 )n is a methylene substituted with a C 1-6  alkyl. 
       
     
     
         61 . The gapmer oligomer of claim  73  wherein (CH 2 )n is a methylene substituted with a methyl group. 
     
     
         62 . The gapmer oligomer of  claim 61  wherein all of the locked nucleotides have the formula: 
       
         
           
           
               
               
           
         
         wherein X is O; (CH 2 )n is a methylene substituted with a methyl group. 
       
     
     
         63 . A LNA antisense oligomer comprising at least one locked nucleotide of formula 
       
         
           
           
               
               
           
         
         wherein X is O; (CH 2 )n is a methylene substituted with a C 1-6  alkyl. 
       
     
     
         64 . The LNA antisense oligomer according to  claim 63  wherein (CH 2 )n is a methylene substituted with a methyl group. 
     
     
         65 . The LNA antisense oligomer according to  claim 63 , wherein at least one or all of the internucleoside linkages are phosphorothioate. 
     
     
         66 . The LNA antisense oligomer according to  claim 63 , which has a length of 10-18 nucleotides. 
     
     
         67 . The LNA antisense oligomer according to  claim 64 , which has a length of 10-18 nucleotides. 
     
     
         68 . The LNA antisense oligomer according to  claim 63  which comprises a central region of at least 8 consecutive DNA nucleotides flanked 5′ and 3′ by regions of locked nucleotides. 
     
     
         69 . The LNA antisense oligomer according to  claim 64  which comprises a central region of at least 8 consecutive DNA nucleotides flanked 5′ and 3′ by regions of locked nucleotides. 
     
     
         70 . The LNA antisense oligomer according to  claim 65  which comprises a central region of at least 8 consecutive DNA nucleotides flanked 5′ and 3′ by regions of locked nucleotides. 
     
     
         71 . The LNA antisense oligomer according to  claim 66  which comprises a central region of at least 8 consecutive DNA nucleotides flanked 5′ and 3′ by regions of locked nucleotides. 
     
     
         72 . The LNA antisense oligomer according to  claim 67  which comprises a central region of at least 8 consecutive DNA nucleotides flanked 5′ and 3′ by regions of locked nucleotides.