# US 11,028,390 B2 · Antisense oligonucleotide controlling expression amount of TDP-43 and use thereof

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- Number: US 11,028,390 B2
- Document ID: US11028390B2
- Status: Granted
- Kind: B2
- Application number: 16/630,141
- Filed: 2018-07-06
- Published: 2020-05-28
- Granted: 2021-06-08
- Earliest claimed: 2017-07-10
- Assignees: Osaka University; Knc Laboratories Co., Ltd.; Aichi Medical University
- Applicants: Osaka University; Knc Laboratories Co., Ltd.; Aichi Medical University
- Inventors: Yoshitaka Nagai; Kazuhiro Maeta; Toshihide Takeuchi; Masahiro Neya; Tsuyoshi Fujihara; Seiji Matsuda; Gen Sobue; Shinsuke Ishigaki; Kentaro Sahashi
- Web page: https://patentgrep.com/patent/US11028390B2

## CPC

- C12N 15/113: 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)}
- A61K 31/712: Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A01K 2207/15: Humanized animals
- A01K 2217/052: inducing gain of function
- A01K 2227/105: Murine
- A01K 2267/0356: Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy
- C12N 2310/11: Antisense
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS

## 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.

## Claims

### Claim 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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).

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 4)

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

### Claim 6 (depends on 1)

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.

### Claim 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.

### Claim 8 (depends on 7)

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

### Claim 9 (depends on 7)

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.

### Claim 10 (depends on 7)

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.

### Claim 11 (depends on 7)

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

### Claim 12 (depends on 1)

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.

### Claim 13 (depends on 7)

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.

### Claim 14 (depends on 1)

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.

### Claim 15 (depends on 1)

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.

### Claim 16 (depends on 15)

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