# US 9,775,331 B2 · Rodent comprising mouse artificial chromosome vector

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- Number: US 9,775,331 B2
- Document ID: US9775331B2
- Status: Granted
- Kind: B2
- Application number: 14/574,749
- Filed: 2014-12-18
- Published: 2015-04-02
- Granted: 2017-10-03
- Earliest claimed: 2010-01-06
- Assignees: National University Corporation Tottori University; Trans Chromosomics, Inc.
- Applicants: National University Corporation Tottori University; Trans Chromosomics, Inc.
- Inventors: Mitsuo Oshimura; Yasuhiro Kazuki; Masato Takiguchi; Takashi Matsuoka
- Web page: https://patentgrep.com/patent/US9775331B2

## CPC

- A01K 67/0278: Knock-in vertebrates, e.g. humanised vertebrates
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- 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
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C12N 15/1086: {Preparation or screening of expression libraries, e.g. reporter assays}
- C12N 15/85: for animal cells
- C12N 15/8509: {for producing genetically modified animals, e.g. transgenic}
- A01K 2207/15: Humanized animals
- A01K 2217/00: Genetically modified animals
- A01K 2217/052: inducing gain of function
- A01K 2217/206: Animal model comprising tissue-specific expression system, e.g. tissue specific expression of transgene, of Cre recombinase
- A01K 2227/105: Murine
- A01K 2267/01: Animal expressing industrially exogenous proteins
- C12N 2800/208: of mammalian origin, e.g. minichromosome
- C12N 2800/30: Vector systems comprising sequences for excision in presence of a recombinase, e.g. loxP or FRT
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Disclosed is a mouse artificial chromosome vector, comprising: a natural centromere derived from a mouse chromosome; a mouse-chromosome-derived long-arm fragment formed by deleting a long-arm distal region at a mouse chromosome long-arm site proximal to the centromere; and a telomere sequence, wherein the vector is stably retained in a cell and/or tissue of a mammal. In addition, disclosed are cells or non-human animals comprising the vector, and use of the cells or non-human animals.

## Claims

### Claim 1

A non-human animal comprising a mouse artificial chromosome vector, wherein the mouse artificial chromosome vector comprises: a natural centromere derived from a mouse chromosome 11; a mouse-chromosome-derived long-arm fragment formed by deleting at least about 99% of all endogenous genes from the long arm of the mouse chromosome 11; and a telomere sequence so as to form the mouse artificial chromosome vector contained in the deposited cell line DT40 B6bT-1 (FERM BP-11128) wherein the vector is stably retained in cells and tissues of the non-human animal at a retention rate of about 90% or more, and wherein the non-human animal is a rodent selected from the group consisting of a mouse and a rat.

### Claim 2 (depends on 1)

The non-human animal according to claim 1, wherein the mouse-chromosome-derived long-arm fragment is formed by deleting at least 99.5% of all endogenous genes from the long arm of the mouse chromosome 11.

### Claim 3 (depends on 1)

The non-human animal according to claim 1, further comprising one or more DNA sequence insertion sites.

### Claim 4 (depends on 3)

The non-human animal according to claim 3, wherein the DNA sequence insertion site is a recognition site for a site-specific recombinase.

### Claim 5 (depends on 3)

The non-human animal according to claim 3, wherein the DNA sequence insertion site is a loxP sequence, an FRT sequence, φC31 attB and φC31 attP sequences, R4 attB and R4 attP sequences, TP901-1 attB and TP901-1 attP sequences, or Bxb1 attB and Bxb1 attP sequences.

### Claim 6 (depends on 1)

The non-human animal according to claim 1, further comprising a reporter gene, a selection marker gene, or both.

### Claim 7 (depends on 1)

The non-human animal according to claim 1, further comprising an exogenous DNA sequence.

### Claim 8 (depends on 1)

The non-human animal according to claim 1, wherein the exogenous DNA sequence has a size of 200 kb or more.

### Claim 9 (depends on 7)

The non-human animal according to claim 7, wherein the exogenous DNA sequence is a human DNA sequence.

### Claim 10 (depends on 7)

The non-human animal according to claim 7, wherein the exogenous DNA sequence is a DNA sequence of a drug-metabolism-related gene.

### Claim 11 (depends on 10)

The non-human animal according to claim 10, wherein the drug-metabolism-related gene is a gene encoding an enzyme involved in a phase I reaction or a phase II reaction.

### Claim 12 (depends on 11)

The non-human animal according to claim 11, wherein the enzyme gene involved in a phase I reaction encodes at least one enzyme selected from the group consisting of CYPs of CYP1A, CYP1B, CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, CYP2J, CYP3A, CYP4A, CYP4B and subfamilies thereof, and CESs.

### Claim 13 (depends on 11)

The non-human animal according to claim 11, wherein the enzyme gene involved in the phase II reaction encodes at least one enzyme selected from the group consisting of UGT1 and UGT2.

### Claim 14 (depends on 10)

The non-human animal according to claim 10, wherein the drug-metabolism-related gene is a gene encoding a transporter.

### Claim 15 (depends on 14)

The non-human animal according to claim 14, wherein the gene encoding the transporter is at least one gene selected from the group consisting of MDR1, MDR2, MRP2, OAT, OATP, OCT, and BCRP.

### Claim 16 (depends on 10)

The non-human animal according to claim 10, wherein the drug-metabolism-related gene is a gene encoding a nuclear receptor.

### Claim 17 (depends on 16)

The non-human animal according to claim 16, wherein the gene encoding the nuclear receptor is at least one gene selected from the group consisting of PXR, AhR, CAR, and PPARα.

### Claim 18 (depends on 7)

The non-human animal according to claim 7, wherein the exogenous DNA sequence is a DNA sequence of a human-chromosome-derived long arm or short arm.

### Claim 19 (depends on 7)

The non-human animal according to claim 7, wherein the exogenous DNA sequence comprises at least two genes selected from the group consisting of genes encoding an enzyme involved in a phase I reaction, genes encoding an enzyme involved in a phase II reaction, genes encoding a transporter, and genes encoding a nuclear receptor.

### Claim 20 (depends on 18)

The non-human animal according to claim 18, wherein the DNA sequence of the human-chromosome-derived long arm or short arm comprises a human chromosome region responsible for a disease gene.

### Claim 21 (depends on 7)

The non-human animal according to claim 7, wherein the exogenous DNA sequence is a gene or DNA sequence encoding a polypeptide selected from the group consisting of cytokines, hormones, growth factors, nutritional factors, hematopoietic factors, coagulation or hemolysis factors, immunoglobulins, G protein-coupled receptors, or enzymes, or a gene or DNA sequence used for treatment involved in a disease.

### Claim 22 (depends on 1)

The non-human animal according to claim 1, wherein the cell is a hepatocyte, enterocyte, renal cell, splenocyte, lung cell, cardiac cell, skeletal muscle cell, brain cell, bone marrow cell, lymphocyte, megakaryocyte, sperm, or ovum.

### Claim 23 (depends on 1)

The non-human animal according to claim 1, wherein the tissue is from a liver, intestine, kidney, spleen, lung, heart, skeletal muscle, brain, bone marrow, testis, or ovary.

### Claim 24 (depends on 21)

The non-human animal according to claim 21, wherein the disease is muscular dystrophy, hemophilia, neurodegenerative disease, autoimmune disease, allergic disease, or genetic disease.