Tau antisense oligomers and uses thereof
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 consisting of the nucleic acid sequence ATTtCcaaattcacTtTtAC (SEQ ID NO:487) or ATtTCcaaattcactTTtAC (SEQ ID NO:472), wherein each upper case letter is a beta-D-oxy-LNA nucleoside, and wherein each lower case letter is a DNA nucleoside.
2. A conjugate comprising the oligomer of claim 1 , wherein the oligomer is covalently attached to at least one non-nucleotide or non-polynucleotide moiety.
3. A pharmaceutical composition comprising the oligomer of claim 1 and a pharmaceutically acceptable diluent, carrier, salt, or adjuvant.
4. The pharmaceutical composition of claim 3 , which is capable of down-regulating expression of the MAPT mRNA in a human cell.
5. The pharmaceutical composition of claim 4 , wherein the human cell is a neuronal cell.
6. A pharmaceutical composition comprising the conjugate of claim 2 and a pharmaceutically acceptable diluent, carrier, salt, or adjuvant.
7. 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 consisting of the nucleic acid sequence ATTtCcaaattcacTtTtAC (SEQ ID NO:487) or ATtTCcaaattcactTTtAC (SEQ ID NO:472), wherein each upper case letter is a beta-D-oxy-LNA nucleoside, and wherein each lower case letter is a DNA nucleoside; or
a conjugate comprising an oligomer having a nucleic acid sequence comprising ATTtCcaaattcacTtTtAC (SEQ ID NO:487) or ATtTCcaaattcactTTtAC (SEQ ID NO:472), wherein each upper case letter is beta-D-oxy-LNA nucleoside, and wherein each lower case letter is a DNA nucleoside, 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.
8. The method of claim 7 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable diluent, carrier, salt, or adjuvant.
9. A method for treating a tauopathy, the method comprising:
administering an effective amount of a pharmaceutical composition comprising at least one of:
an oligomer consisting of the nucleic acid sequence ATTtCcaaattcacTtTtAC (SEQ ID NO:487) or ATtTCcaaattcactTTtAC (SEQ ID NO:472), wherein each upper case letter is a beta-D-oxy-LNA nucleoside, and wherein each lower case letter is a DNA nucleoside; or
a conjugate comprising an oligomer consisting of the nucleic acid sequence ATTtCcaaattcacTtTtAC (SEQ ID NO:487) or ATtTCcaaattcactTTtAC (SEQ ID NO:472), wherein each upper case letter is a beta-D-oxy-LNA nucleoside, and wherein each lower case letter is a DNA nucleoside, wherein the oligomer is covalently attached to at least one non-nucleotide or non-polynucleotide moiety.
10. The method of claim 9 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable diluent, carrier, salt, or adjuvant.
11. 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 consisting of the nucleic acid sequence ATTtCcaaattcacTtTtAC (SEQ ID NO:487) or ATtTCcaaattcactTTtAC (SEQ ID NO:472), wherein each upper case letter is a beta-D-oxy-LNA nucleoside, and wherein each lower case letter is a DNA nucleoside; or
a conjugate comprising an oligomer consisting of the nucleic acid sequence ATTtCcaaattcacTtTtAC (SEQ ID NO:487) or ATtTCcaaattcactTTtAC (SEQ ID NO:472), wherein each upper case letter is a beta-D-oxy-LNA nucleoside, and wherein each lower case letter is a DNA nucleoside, wherein the oligomer is covalently attached to at least one non-nucleotide
or non-polynucleotide moiety.
12. The method of claim 11 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable diluent, carrier, salt, or adjuvant.
13. The method of claim 11 , wherein the disorder associated with over expression or expression of a mutated version of Tau protein is a tauopathy.