Oligonucleotides for modulating tau expression

Abstract

The present invention relates to antisense oligonucleotides that are capable of modulating expression of Tau in a target cell. The oligonucleotides hybridize to MAPT mRNA. The present invention further relates to conjugates of the oligonucleotide and pharmaceutical compositions and methods for treatment of Tauopathies, Alzheimer's disease, fronto-temporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), epilepsy, Dravet syndrome, depression, seizure disorders and movement disorders.

1 . An antisense oligonucleotide of 10 to 30 nucleotides in length, which comprises a contiguous nucleotide sequence of at least 10 nucleotides in length with at least 90% complementarity, to contiguous nucleotides within position 12051 to 12111, 39562 to 39593, or 72837 to 72940 of SEQ ID NO: 1. 
     
     
         2 . The antisense oligonucleotide of  claim 1 , wherein the contiguous nucleotide sequence is at least 16 nucleotides and 100% complementary to contiguous nucleotides within position 12060 to 12078, 39573 to 39592, or position 72862-72890 of SEQ ID NO: 1. 
     
     
         3 . The antisense oligonucleotide of  claim 1 , wherein the oligonucleotide comprises a sequence selected from the group consisting of SEQ ID NO: 9, 11, 49, 53, 56, and 62. 
     
     
         4 . The antisense oligonucleotide of  claim 1 , wherein the oligonucleotide is capable of reducing the expression of Tau. 
     
     
         5 . The antisense oligonucleotide of  claim 1 , wherein the contiguous nucleotide sequence comprises one or more 2′ sugar modified nucleosides. 
     
     
         6 . The antisense oligonucleotide of  claim 5 , wherein the one or more 2′ sugar modified nucleoside is independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic acid (ANA), 2′-fluoro-ANA, and LNA nucleosides. 
     
     
         7 . The antisense oligonucleotide of  claim 1 , wherein the contiguous nucleotide sequence comprises 4 to 8 LNA nucleosides. 
     
     
         8 . The antisense oligonucleotide of  claim 1 , wherein at least 80% of the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate internucleoside linkages. 
     
     
         9 . The antisense oligonucleotide of  claim 1 , wherein the oligonucleotide is capable of recruiting RNase H. 
     
     
         10 . The antisense oligonucleotide of  claim 9 , wherein the antisense oligonucleotide, or contiguous nucleotide sequence thereof, consists or comprises a gapmer of formula 5′-F-G-F′-3′, where region F and F′ independently comprise 1-8 nucleosides, of which 2-5 are 2′ sugar modified and defines the 5′ and 3′ end of the F and F′ region, and the G is a region between 6 and 16 nucleosides which is capable of recruiting RnaseH. 
     
     
         11 . The antisense oligonucleotide of  claim 1 , wherein the antisense oligonucleotide is a compound selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 9; CMP ID NO: 9_102) 
                 
                     
                   CTTtAATttaatcactcAT; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 9; CMP ID NO: 9_103) 
                 
                     
                   CTTTaatttaatcacTCAT; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 9; CMP ID NO: 9_104) 
                 
                     
                   CTTTaatttaatcaCtCAT; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 11; CMP ID NO: 11_1) 
                 
                     
                   CTTTaatttaatcaCTCA; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 49; CMP ID NO: 49_38) 
                 
                     
                   TtaaCTCAaatcaaTtctCA; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 49; CMP ID NO: 49_51) 
                 
                     
                   TtaActCAaatcaattCTCA; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 49; CMP ID NO: 49_179) 
                 
                     
                   TTAactCaaatcaatTCtCA; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 49; CMP ID NO: 49_189) 
                 
                     
                   TTAActcaaatcaattCTCA; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 53; CMP ID NO: 53_1) 
                 
                     
                   CAACaccttttaattcATTA; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 56; CMP ID NO: 56_1) 
                 
                     
                   CTCAtcaacaccttttaaTT; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 62; CMP ID NO: 62_1), 
                 
                     
                   TTAactcatcaacaCCTT  
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein capital letters are beta-D-oxy LNA nucleosides, lowercase letters are DNA nucleosides, all LNA C are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate internucleoside linkages. 
       
     
     
         12 . The antisense oligonucleotide of  claim 1 , wherein the antisense oligonucleotide is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The antisense oligonucleotide of  claim 1 , wherein the antisense oligonucleotide is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The antisense oligonucleotide of  claim 1 , wherein the antisense oligonucleotide is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The antisense oligonucleotide of  claim 1 , wherein the antisense oligonucleotide is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The antisense oligonucleotide of  claim 1 , wherein the antisense oligonucleotide is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A conjugate comprising the antisense oligonucleotide of  claim 1 , and at least one conjugate moiety covalently attached to said oligonucleotide. 
     
     
         18 . A pharmaceutically acceptable salt of the antisense oligonucleotide of  claim 1 , or a conjugate comprising the antisense oligonucleotide of  claim 1 . 
     
     
         19 . A pharmaceutical composition comprising the antisense oligonucleotide of  claim 1  or a conjugate comprising the antisense oligonucleotide of  claim 1 , and a pharmaceutically acceptable diluent, solvent, carrier, salt, and/or adjuvant. 
     
     
         20 . An in vivo or in vitro method for modulating Tau expression in a target cell which is expressing Tau, said method comprising administering an antisense oligonucleotide of  claim 1 , a conjugate comprising the antisense oligonucleotide of  claim 1 , or a pharmaceutical composition comprising the antisense oligonucleotide of  claim 1  in an effective amount to said cell. 
     
     
         21 . A method for treating or preventing a disease comprising administering a therapeutically or prophylactically effective amount of an antisense oligonucleotide of  claim 1 , a conjugate comprising the antisense oligonucleotide of  claim 1 , or a pharmaceutical composition comprising the antisense oligonucleotide of  claim 1 , to a subject suffering from or susceptible to the disease. 
     
     
         22 . The method of  claim 21 , wherein the disease is selected from the group consisting of Alzheimer's disease (AD), progressive supranuclear palsy (PSP), fronto-temporal dementia (FTD) or FTD with parkinsonism linked to chromosome 17 (FTDP-17). 
     
     
         23 . The method of  claim 22 , wherein the disease is PSP. 
     
     
         24 . The method of  claim 22 , wherein the disease is AD. 
     
     
         25 - 27 . (canceled) 
     
     
         28 . The antisense oligonucleotide of  claim 10 , wherein the G is a region comprising 6-16 DNA nucleosides.