Tau antisense oligomers and uses thereof

Abstract

The present invention relates to oligomer compounds (oligomers), which target Tau mRNA in a cell, leading to reduced expression of Tau protein. Reduction of Tau protein expression is beneficial for the treatment of certain medical disorders, e.g., a neurological disorder.

1 . An oligomer of from 10 to 50 nucleotides in length comprising a contiguous nucleotide sequence that hybridizes to a nucleic acid sequence within a microtubule-associated protein tau (MAPT) transcript, wherein the nucleic acid sequence corresponds to nucleotides 138884-138903 of SEQ ID NO:1. 
     
     
         2 . The oligomer of  claim 1 , wherein the contiguous nucleotide sequence is 10 to 20 nucleotides in length. 
     
     
         3 . The oligomer of  claim 1 , wherein the contiguous nucleotide sequence comprises at least one sugar modified nucleoside analog. 
     
     
         4 . The oligomer of  claim 1 , which is a gapmer, a blockmer, a mixmer, a headmer, a tailmer, or a totalmer. 
     
     
         5 . The oligomer of  claim 1 , which has the formula of 5′-A-B-C-3′ (I), wherein
 (i) B is a contiguous sequence of 7 to 23 DNA units; 
 (ii) A is a first wing sequence of 1 to 10 nucleotides, wherein the first wing sequence comprises one or more nucleotide analogs and optionally one or more DNA units and wherein at least one of the nucleotide analogs is located at the 5′ end of A; and 
 (iii) C is a second wing sequence of 1 to 10 nucleotides, wherein the second wing sequence comprises one or more nucleotide analogs and optionally one or more DNA units and wherein at least one of the nucleotide analogs is located at the 3′ end of C. 
 
     
     
         6 . The oligomer of  claim 5 , wherein A is selected from L, LL, LDL, LLL, LLLL, LLDL, LDLL, LDDL, LLDD, LLLLL, LLLDL, LLDLL, LDLLL, LLDDL, LDDLL, LLDLD, LDLLD, LDLDL, LDDDL, LLLLLL, LLLLDL, LLLDLL, LLDLLL, LDLLLL, LLLDDL, LLDLDL, LLDDLL, LDDLLL, LDLLDL, LDLDLL, LDDDLL, LLDDDL, and LDLDLD, and C is selected from L, LL, LDL, LLL, LLLL, LLDL, LDLL, LDDL, LLDD, LLLLL, LLLDL, LLDLL, LDLLL, LLDDL, LDDLL, LLDLD, LDLLD, LDLDL, LDDDL, LLLLLL, LLLLDL, LLLDLL, LLDLLL, LDLLLL, LLLDDL, LLDLDL, LLDDLL, LDDLLL, LDLLDL, LDLDLL, LDDDLL, LLDDDL, and LDLDLD, wherein L is a sugar modified nucleoside analog, and wherein D is a DNA nucleoside. 
     
     
         7 . The oligomer of  claim 3 , wherein the sugar modified nucleoside analog or analogs are selected from Locked Nucleic Acid (LNA); 2′-0-alkyl-RNA; 2′-amino-DNA; 2′-fluoro-DNA; arabino nucleic acid (ANA); 2′-fluoro-ANA, hexitol nucleic acid (HNA), intercalating nucleic acid (INA), constrained ethyl nucleoside (cEt), 2′-0-methyl nucleic acid (2′-OMe), 2′-0-methoxyethyl nucleic acid (2′-MOE), and any combination thereof. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The oligomer of  claim 1 , wherein the contiguous nucleotide sequence has at least about 80% sequence identity to the sequence atttccaaattcacttttac (SEQ ID NO:466). 
     
     
         11 . The oligomer of  claim 1 , wherein the oligomer has a design selected from the group consisting of ATTtCcaaattcacTtTtAC (SEQ ID NO:487) and AtTTCcaaattcactTTtAC (SEQ ID NO:473), wherein an upper case letter is a sugar modified nucleoside analog, and wherein a lower case letter is a DNA nucleoside. 
     
     
         12 - 16 . (canceled) 
     
     
         17 . A conjugate comprising the oligomer of  claim 1 , wherein the oligomer is covalently attached to at least one non-nucleotide or non-polynucleotide moiety. 
     
     
         18 . A pharmaceutical composition comprising the oligomer of  claim 1  and a pharmaceutically acceptable diluent, carrier, salt, or adjuvant. 
     
     
         19 - 22 . (canceled) 
     
     
         23 . The oligomer of  claim 3 , wherein the sugar modified nucleoside analog or analogs comprise a bicyclic sugar and are selected from cEt, 2′,4′-constrained 2′-O-methoxyethyl (cMOE), α-LNA, β-LNA, 2′-O,4′-C-ethylene-bridged nucleic acids (ENA), amino-LNA, oxy-LNA, or thio-LNA. 
     
     
         24 . The oligomer of  claim 3 , wherein the sugar modified nucleoside analog or analogs are beta-D-oxy-LNA nucleosides. 
     
     
         25 . The oligomer of  claim 1 , wherein the oligomer has the chemical structure: 5′ OxyAs DNAts OxyTs OxyTs OxyMCs DNAcs DNAas DNAas DNAas DNAts DNAts DNAcs DNAas DNAcs DNAts OxyTs OxyTs DNAts OxyAs OxyMC 3′, wherein OxyA designates a beta-D-oxy-LNA adenine nucleoside, OxyT designates a beta-D-oxy-LNA thymine nucleoside, OxyG designates a beta-D-oxy-LNA guanine nucleoside, OxyMC designates a beta-D-oxy-LNA 5-methyl cytosine nucleoside, DNAa designates a DNA adenine nucleoside, DNAt designates a DNA thymine nucleoside, DNAg designates a DNA guanine nucleoside, and s designates a phosphorothioate internucleoside linkage. 
     
     
         26 . The oligomer of  claim 1 , wherein the oligomer is 5′ OxyAs OxyTs OxyTs DNAts OxyMCs DNAcs DNAas DNAas DNAas DNAts DNAts DNAcs DNAas DNAcs OxyTs DNAts OxyTs DNAts OxyAs OxyMC 3′, wherein OxyA designates a beta-D-oxy-LNA adenine nucleoside, OxyT designates a beta-D-oxy-LNA thymine nucleoside, OxyG designates a beta-D-oxy-LNA guanine nucleoside, OxyMC designates a beta-D-oxy-LNA 5-methyl cytosine nucleoside, DNAa designates a DNA adenine nucleoside, DNAt designates a DNA thymine nucleoside, DNAg designates a DNA guanine nucleoside, and s designates a phosphorothioate internucleoside linkage. 
     
     
         27 . The oligomer of  claim 1 , which is capable of down-regulating expression of the MAPT mRNA in a human cell. 
     
     
         28 . The oligomer of  claim 27 , wherein the human cell is a neuronal cell. 
     
     
         29 . A pharmaceutical composition comprising the conjugate of  claim 17  and a pharmaceutically acceptable diluent, carrier, salt, or adjuvant. 
     
     
         30 . A method of inhibiting or reducing Tau protein expression in a cell, the method comprising:
 administering a pharmaceutical composition comprising at least one of:
 an oligomer of from 10 to 50 nucleotides in length comprising a contiguous nucleotide sequence that hybridizes to a nucleic acid sequence within a microtubule-associated protein tau (MAPT) transcript, wherein the nucleic acid sequence corresponds to nucleotides 138884-138903 of SEQ ID NO:1; or 
 a conjugate comprising an oligomer of from 10 to 50 nucleotides in length comprising a contiguous nucleotide sequence that hybridizes to a nucleic acid sequence within a microtubule-associated protein tau (MAPT) transcript, wherein the nucleic acid sequence corresponds to nucleotides 138884-138903 of SEQ ID NO:1, wherein the oligomer is covalently attached to at least one non-nucleotide or non-polynucleotide moiety; 
   to the cell expressing Tau protein, wherein the Tau protein expression in the cell is inhibited or reduced after the administration.   
     
     
         31 . The method of  claim 30 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable diluent, carrier, salt, or adjuvant. 
     
     
         32 . A method for treating or preventing a neurological disorder, the method comprising:
 administering an effective amount of a pharmaceutical composition comprising at least one of:
 an oligomer of from 10 to 50 nucleotides in length comprising a contiguous nucleotide sequence that hybridizes to a nucleic acid sequence within a microtubule-associated protein tau (MAPT) transcript, wherein the nucleic acid sequence corresponds to nucleotides 138884-138903 of SEQ ID NO:1; or 
 a conjugate comprising an oligomer of from 10 to 50 nucleotides in length comprising a contiguous nucleotide sequence that hybridizes to a nucleic acid sequence within a microtubule-associated protein tau (MAPT) transcript, wherein the nucleic acid sequence corresponds to nucleotides 138884-138903 of SEQ ID NO:1, wherein the oligomer is covalently attached to at least one non-nucleotide or non-polynucleotide moiety. 
   
     
     
         33 . The method of  claim 32 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable diluent, carrier, salt, or adjuvant. 
     
     
         34 . A method for treating a disorder associated with over expression or expression of a mutated version of Tau protein, the method comprising:
 administering an effective amount of a pharmaceutical composition comprising at least one of:
 an oligomer of from 10 to 50 nucleotides in length comprising a contiguous nucleotide sequence that hybridizes to a nucleic acid sequence within a microtubule-associated protein tau (MAPT) transcript, wherein the nucleic acid sequence corresponds to nucleotides 138884-138903 of SEQ ID NO:1; or 
 a conjugate comprising an oligomer of from 10 to 50 nucleotides in length comprising a contiguous nucleotide sequence that hybridizes to a nucleic acid sequence within a microtubule-associated protein tau (MAPT) transcript, wherein the nucleic acid sequence corresponds to nucleotides 138884-138903 of SEQ ID NO:1, wherein the oligomer is covalently attached to at least one non-nucleotide or non-polynucleotide moiety. 
   
     
     
         35 . The method of  claim 34 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable diluent, carrier, salt, or adjuvant. 
     
     
         36 . The method of  claim 34 , wherein the disorder associated with over expression or expression of a mutated version of Tau protein is a tauopathy. 
     
     
         37 . The oligomer of  claim 10 , wherein the contiguous nucleotide sequence has at least about 90% sequence identity to the sequence atttccaaattcacttttac (SEQ ID NO:466). 
     
     
         38 . The oligomer of  claim 37 , wherein the contiguous nucleotide sequence has at least about 95% sequence identity to the sequence atttccaaattcacttttac (SEQ ID NO:466). 
     
     
         39 . The oligomer of  claim 38 , wherein the contiguous nucleotide sequence has at least about 96% sequence identity to the sequence atttccaaattcacttttac (SEQ ID NO:466). 
     
     
         40 . The oligomer of  claim 39 , wherein the contiguous nucleotide sequence has at least about 97% sequence identity to the sequence atttccaaattcacttttac (SEQ ID NO:466). 
     
     
         41 . The oligomer of  claim 40 , wherein the contiguous nucleotide sequence has at least about 98% sequence identity to the sequence atttccaaattcacttttac (SEQ ID NO:466). 
     
     
         42 . The oligomer of  claim 41 , wherein the contiguous nucleotide sequence has at least about 99% sequence identity to the sequence atttccaaattcacttttac (SEQ ID NO:466). 
     
     
         43 . The oligomer of  claim 42 , wherein the contiguous nucleotide sequence has 100% sequence identity to the sequence atttccaaattcacttttac (SEQ ID NO:466).