Antisense oligonucleotide controlling expression amount of TDP-43 and use thereof

Patent metadata

Field	Value
Publication number	US-11028390-B2
Application number	US-201816630141-A
Country	US
Kind code	B2
Filing date	Jul 6, 2018
Priority date	Jul 10, 2017
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

Abstract

The present invention provides a suppression type antisense oligonucleotide targeting TDP-43 mRNA, containing a nucleotide sequence complementary to a sequence consisting of at least 10 continuous nucleotides in a nucleotide sequence shown in any of SEQ ID NOs: 2-4, and a promotion type antisense oligonucleotide targeting TDP-43 mRNA, containing a nucleotide sequence complementary to a sequence consisting of at least 10 continuous nucleotides in a nucleotide sequence shown in SEQ ID NO: 5.

First claim

The invention claimed is:

1. An antisense oligonucleotide targeting TAR DNA-binding domain 43 (TDP-43) mRNA, comprising a nucleotide sequence complementary to a sequence consisting of at least 15 continuous nucleotides in the nucleotide sequence of any of SEQ ID NOs: 2-4, wherein the oligonucleotide comprises modification of one or more kinds of sugar-phosphoric acid backbone.

2. The antisense oligonucleotide according to claim 1 , wherein the oligonucleotide consists of 15-30 nucleotides.

3. The antisense oligonucleotide according to claim 1 , wherein the complementary nucleotide sequence is the nucleotide sequence of any of SEQ ID NOs: 45-63 (wherein thymine may be uracil).

4. The antisense oligonucleotide according to claim 1 , wherein the oligonucleotide comprises 2′-O,4′-C-ethylene-bridged nucleic acid and deoxyribonucleotide.

5. The antisense oligonucleotide according to claim 4 , wherein the oligonucleotide is of a gapmer type.

6. The antisense oligonucleotide according to claim 1 , wherein the oligonucleotide consists of the nucleotide sequence of any of SEQ ID NOs: 11, 22-29 and 35-44.

7. An antisense oligonucleotide targeting TAR DNA-binding domain 43 (TDP-43) mRNA, comprising a nucleotide sequence complementary to a sequence consisting of at least 15 continuous nucleotides in the nucleotide sequence of SEQ ID NO: 5, wherein the oligonucleotide comprises modification of one or more kinds of sugar-phosphoric acid backbone.

8. The antisense oligonucleotide according to claim 7 , wherein the oligonucleotide consists of 15-30 nucleotides.

9. The antisense oligonucleotide according to claim 7 , wherein the oligonucleotide comprises 2′-O,4′-C-ethylene-bridged nucleic acid and 2′-O-methyl-modified nucleic acid.

10. The antisense oligonucleotide according to claim 7 , wherein the cytosine nucleotide and thymine nucleotide are 2′-O,4′-C-ethylene-bridged nucleic acids, and adenine nucleotide and guanine nucleotide are 2′-O-methyl-modified nucleic acids.

11. The antisense oligonucleotide according to claim 7 , wherein the oligonucleotide consists of the nucleotide sequence of SEQ ID NO: 84, 85 or 87.

12. The antisense oligonucleotide according to claim 1 , comprising a nucleotide sequence complementary to a sequence consisting of at least 19 continuous nucleotides in the nucleotide sequence of any of SEQ ID NOs: 2-4.

13. The antisense oligonucleotide according to claim 7 , comprising a nucleotide sequence complementary to a sequence consisting of at least 19 continuous nucleotides in the nucleotide sequence of SEQ ID NO: 5.

14. A method for regulating expression of TDP-43, comprising administering an effective amount of the antisense oligonucleotide according to claim 1 in vivo or in vitro.

15. A method for treating TDP-43 proteinopathy in a mammal, comprising administering an effective amount of the antisense oligonucleotide according to claim 1 to the mammal.

16. The method according to claim 15 , wherein the TDP-43 proteinopathy is amyotrophic lateral sclerosis or frontotemporal dementia.

Assignees

• Univ Osaka
• Knc Laboratories Co Ltd
• Aichi Medical Univ

Inventors

• Nagai Yoshitaka
• Maeta Kazuhiro
• Takeuchi Toshihide
• Neya Masahiro
• Fujihara Tsuyoshi
• Matsuda Seiji
• Sobue Gen
• Ishigaki Shinsuke
• Sahashi Kentaro

Classifications

• C12N2310/341

  Gapmers, i.e. of the type ===---=== · CPC title

• C12N2310/3231

  having an additional ring, e.g. LNA, ENA · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• A01K2267/0356

  Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy · CPC title