Modified oligonucleotides for use in treatment of tauopathies

Abstract

Oligonucleotides comprising modifications at the 2′ and/or 3′ positions(s) along with methods of making and use against Alzheimer disease and other tauopathies are disclosed.

What is claimed is: 
     
         1 . An oligonucleotide complimentary to at least a portion of the MAPT gene comprising one or more nucleotides of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R is H or a positively charged counter ion, 
         B is a nucleobase, 
         R 1  is —(CR′ 2 ) 2 OCR′ 3 , and 
         R′ is independently in each instance H or F. 
       
     
     
         2 . The oligonucleotide of  claim 1 , wherein each nucleotide of said oligonucleotide is a nucleotide of Formula (I). 
     
     
         3 . The oligonucleotide of  claim 1 , wherein the oligonucleotide comprises 2 to 40 nucleotides. 
     
     
         4 . The oligonucleotide of  claim 1 , wherein the oligonucleotide comprises 2-26 nucleotides of Formula (I). 
     
     
         5 . The oligonucleotide of  claim 1 , wherein the oligonucleotide comprises 5-10 nucleotides of Formula (I). 
     
     
         6 - 88 . (canceled) 
     
     
         89 . A pharmaceutical composition comprising an oligonucleotide of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         90 . The pharmaceutical composition of claim  0 , wherein the composition is suitable for intrathecal or intracerebroventricular delivery. 
     
     
         91 . A method of inhibiting MAPT gene expression in a CNS cell comprising contacting the cell with an oligonucleotide or composition of  claim 1 . 
     
     
         92 . A method of inhibiting transcription of MAPT mRNA in a CNS cell comprising contacting the cell with an oligonucleotide or composition of  claim 1 . 
     
     
         93 . A method of treating a subject having tauopathy, comprising administering to the subject a therapeutically effective amount of an oligonucleotide or composition of  claim 1 . 
     
     
         94 . The method of  claim 93 , wherein the tauopathy is Alzheimer's disease. 
     
     
         95 . The oligonucleotide of  claim 1 , wherein said oligonucleotide complexed with an MAPT gene has a melting temperature (Tm) of >37° C. 
     
     
         96 . A method of treating a subject having tauopathy, comprising administering to the subject a therapeutically effective amount of an oligonucleotide or composition of  claim 1 . 
     
     
         97 . The method of  claim 96 , wherein the tauopathy is Alzheimer's disease. 
     
     
         98 . A method of inhibiting expression of a MAPT mRNA in a CNS cell comprising contacting the cell with an oligonucleotide or composition comprising an oligonucleotide of  claim 1 , wherein the oligonucleotide contains a nucleobase sequence that is complementary or hybridizes to at least a portion of the MAPT mRNA. 
     
     
         99 . A method of treating a subject having tauopathy, comprising administering to the subject a therapeutically effective amount of an oligonucleotide or composition comprising said oligonucleotide of  claim 1 , wherein the oligonucleotide contains a nucleobase sequence that is complementary or hybridizes to at least a portion of the MAPT gene sequence. 
     
     
         100 . The method of  claim 99 , wherein the tauopathy is Alzheimer's disease. 
     
     
         101 . A method of modulating expression of a MAPT gene by contacting a target nucleic acid with an antisense compound comprising an oligonucleotide or composition comprising said oligonucleotide of  claim 1 , wherein the oligonucleotide contains a nucleobase sequence that is complementary or hybridizes to at least a portion of the MAPT gene. 
     
     
         102 . The method of  claim 101 , wherein the portion of the MAPT gene is exon 5, exon 10, or exon 12.