# US 11,895,993 B2 · Method of producing a novel animal model for tauopathies

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- Number: US 11,895,993 B2
- Document ID: US11895993B2
- Status: Granted
- Kind: B2
- Application number: 16/805,203
- Filed: 2020-02-28
- Published: 2020-09-17
- Granted: 2024-02-13
- Earliest claimed: 2019-03-01
- Assignees: Tokyo Metropolitan Institute of Medical Science
- Applicants: Tokyo Metropolitan Institute of Medical Science
- Inventors: Masato Hosokawa; Hiroshi Shitara; Masato Hasegawa
- Web page: https://patentgrep.com/patent/US11895993B2

## CPC

- A01K 67/027: New or modified breeds of vertebrates
- A01K 67/0275: Genetically modified vertebrates, e.g. transgenic
- C07K 14/47: from mammals
- C07K 14/4711: {Alzheimer's disease; Amyloid plaque core protein}
- C12N 5/10: Cells modified by introduction of foreign genetic material
- C12N 15/01: Preparation of mutants without inserting foreign genetic material therein; Screening processes therefor
- G01N 33/5088: {of vertebrates}
- G01N 33/68: involving proteins, peptides or amino acids {(involving lipoproteins G01N33/92)}
- A01K 2207/10: Animals modified by protein administration, for non-therapeutic purpose
- A01K 2207/15: Humanized animals
- A01K 2217/072: maintaining or altering function, i.e. knock in
- A01K 2227/105: Murine
- A01K 2267/0318: Animal model for neurodegenerative disease, e.g. non- Alzheimer's
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention provides a disease model animal for tauopathies which reproduces the expression pattern of tau protein isoforms of adult human brain, that is, approximately equal amounts of 3R type tau and 4R type tau being expressed in the adult brain. The method for producing the disease model animal for tauopathies of the present invention comprises the steps of: preparing a tau seeds; and injecting the tau seeds in the brain of an animal carrying a mutation in the tau gene which fails to express the tenth exon. The animal carrying a mutation in the tau gene which fails to express the tenth exon may be produced by using any of the genome editing, gene targeting or base editing technologies.

## Claims

### Claim 1

A method for producing a disease model animal for a human sporadic tauopathy, comprising the steps of:
injecting a composition comprising tau seeds obtained from a brain of a human patient afflicted with the human sporadic tauopathy in the brain of a mouse, wherein the genome of the mouse is hemizygous for an endogenous tau gene that is modified between exon 10 and intron 10 whereby exon 10 is not expressed, and the mouse expresses both 3R and 4R type tau isoforms in the brain.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the composition comprises a sarkosyl insoluble fraction derived from the brain of the human patient.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the pathological tau fibrils in the brain are characterized by at least one property selected from the group consisting of: the type composition of tau protein comprised in the pathological tau fibrils, the phosphorylation state of the tau protein, and Gallyas-Braak silver stainability of brain tissues comprising the pathological tau fibrils.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the endogenous tau gene that is modified comprises SEQ ID NO:1 or SEQ ID NO:2.

### Claim 5 (depends on 4)

The method according to claim 4, wherein the nucleotide sequence was introduced into the genome of the mouse using genome editing, gene targeting, or base editing technology.

### Claim 6 (depends on 1)

A disease model animal for a human sporadic tauopathy produced by the method according to claim 1.

### Claim 7 (depends on 1)

An animal brain which is dissected from the disease model animal produced by the method according to claim 1.

### Claim 8 (depends on 1)

A method for analyzing the disease model animal produced by the method according to claim 1, comprising the steps of:
dissecting the brain of the disease model animal; and
characterizing the pathological tau fibrils in the dissected brain.