# US 12,274,247 B2 · Genetically modified rat models for severe combined immunodeficiency (SCID)

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- Number: US 12,274,247 B2
- Document ID: US12274247B2
- Status: Granted
- Kind: B2
- Application number: 17/335,568
- Filed: 2021-06-01
- Published: 2021-12-23
- Granted: 2025-04-15
- Earliest claimed: 2009-07-01
- Assignees: Hera Testing Laboratories, Inc.
- Applicants: Hera Testing Laboratories, Inc.
- Inventors: Eric M. Ostertag; John Stuart Crawford; Joseph Ruiz
- Web page: https://patentgrep.com/patent/US12274247B2

## CPC

- A01K 67/0276: Knock-out vertebrates
- C12N 9/1205: {Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases}
- C12N 9/14: Hydrolases (3)
- C12N 9/22: Ribonucleases {[RNase]; Deoxyribonucleases [DNase]}
- C12N 15/8509: {for producing genetically modified animals, e.g. transgenic}
- C12N 15/87: Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N 15/907: {in mammalian cells}
- A01K 2217/05: Animals comprising random inserted nucleic acids (transgenic)
- A01K 2217/054: inducing loss of function
- A01K 2217/056: due to mutation of coding region of the transgene (dominant negative)
- A01K 2217/15: Animals comprising multiple alterations of the genome, by transgenesis or homologous recombination, e.g. obtained by cross-breeding
- A01K 2217/20: Animal model comprising regulated expression system
- 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 2267/0331: Animal model for proliferative diseases
- A01K 2267/0387: Animal model for diseases of the immune system
- C12N 2015/8536: {Animal models for genetic diseases}
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

This invention relates to the engineering of animal cells, preferably mammalian, more preferably rat, that are deficient due to the disruption of tumor suppressor gene(s) or gene product(s). In another aspect, the invention relates to genetically modified rats, as well as the descendants and ancestors of such animals, which are animal models of human cancer and methods of their use.

## Claims

### Claim 1

A genetically engineered rat, or progeny of the rat, whose genome comprises a homozygous knock-out of the Il2rg gene and a homozygous knock-out of the Rag2 gene that results in decreased or eliminated Il2rg and Rag2 gene product activity,
wherein the rat or its progeny comprises a knock-in of a SIRPα gene,
wherein the rat or its progeny exhibits Severe Combined Immunodeficiency (SCID), wherein the rat or its progeny has decreased levels of mature T-cells, B-cells and NK-cells, as compared to a rat not comprising the knock-out of the Il2rg gene and the knock-out of the Rag2 gene.

### Claim 2 (depends on 1)

The genetically engineered rat, or progeny of the rat, of claim 1, wherein the SIRPα gene comprises a heterologous SIRPα exon.

### Claim 3 (depends on 1)

The genetically engineered rat, or progeny of the rat, of claim 1, wherein the rat or its progeny lacks mature B-cells, T-cells, and NK-cells.

### Claim 4 (depends on 1)

The genetically engineered rat, or progeny of the rat, of claim 1, wherein the rat or its progeny is capable of accepting a tumor xenograft without eliciting an immune response.

### Claim 5 (depends on 1)

The genetically engineered rat, or progeny of the rat, of claim 1, wherein the rat or its progeny comprises a xenograft.

### Claim 6 (depends on 5)

The genetically engineered rat, or progeny of the rat, of claim 5, wherein the xenograft is from human lymphoid or myeloid tissues.

### Claim 7 (depends on 5)

The genetically engineered rat, or progeny of the rat, of claim 5, wherein the xenograft is from human peripheral blood lymphocytes.

### Claim 8 (depends on 5)

The genetically engineered rat, or progeny of the rat, of claim 5, wherein the xenograft is from human thymus.

### Claim 9 (depends on 5)

The genetically engineered rat, or progeny of the rat, of claim 5, wherein the xenograft is from human liver tissue.

### Claim 10 (depends on 1)

The genetically engineered rat, or progeny of the rat, of claim 1, wherein the rat or its progeny comprises transplanted human cells.

### Claim 11 (depends on 10)

The genetically engineered rat, or progeny of the rat, of claim 10, wherein the transplanted human cells are primary cells from healthy subjects or from subjects with genetic lesions associated with disease states.

### Claim 12 (depends on 1)

The genetically engineered rat, or progeny of the rat, of claim 1, wherein the rat or its progeny comprises transplanted stem cells.

### Claim 13 (depends on 1)

The genetically engineered rat, or progeny of the rat, of claim 1, wherein the homozygous knock-out of the Il2rg gene and the homozygous knock-out of the Rag2 gene results in eliminated Il2rg and Rag2 gene product activity.

### Claim 14 (depends on 2)

The genetically engineered rat, or progeny of the rat, of claim 2, wherein the SIRPα gene comprises a heterologous SIRPα exon and one or more heterologous regulatory DNA sequences.

### Claim 15 (depends on 14)

The genetically engineered rat, or progeny of the rat, of claim 14, wherein the heterologous SIRPα exon encodes a SIRPα fusion protein.

### Claim 16 (depends on 5)

The genetically engineered rat, or progeny of the rat, of claim 5, wherein the xenograft is a tumor xenograft or healthy tissue xenograft.

### Claim 17 (depends on 12)

The genetically engineered rat, or progeny of the rat, of claim 12, wherein the stem cells are hematopoietic stem cells.