# US 2026/0076346 A1 · Immunodeficient non-human animals for assessing drug metabolism and toxicity > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2026/0076346 A1 - Document ID: US20260076346A1 - Status: Published application - Kind: A1 - Application number: 19/109,590 - Filed: 2023-09-08 - Published: 2026-03-19 - Earliest claimed: 2022-09-08 - Assignees: University of Dundee - Applicants: University of Dundee - Inventors: Roland WOLF; Colin HENDERSON - Web page: https://patentgrep.com/patent/US20260076346A1 ## CPC - A01K 67/0275: Genetically modified vertebrates, e.g. transgenic - G01N 33/5011: {for testing antineoplastic activity} - G01N 33/5088: {of vertebrates} - A01K 2207/12: Animals modified by administration of exogenous cells - A01K 2207/15: Humanized animals - A01K 2217/075: inducing loss of function, i.e. knock out - A01K 2217/15: Animals comprising multiple alterations of the genome, by transgenesis or homologous recombination, e.g. obtained by cross-breeding - A01K 2227/105: Murine - A01K 2267/0331: Animal model for proliferative diseases - A01K 2267/0337: Animal models for infectious diseases - A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS - 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 relates to an immunodeficient non-human animal where endogenous drug metabolising enzymes and transcription factors are substantially inactivated. In some aspects of the invention, the animal expresses human drug metabolising enzymes and associated transcription factors. There is also provided related methods of generating the animal of the invention. Additionally, there is provided methods of performing preclinical drug studies using the animal of the invention. ## Claims ### Claim 1 An immunodeficient non-human animal wherein at least one endogenous drug metabolism enzyme has been substantially inactivated. ### Claim 2 (depends on 1) The immunodeficient non-human animal according to claim 1, wherein the at least one endogenous drug metabolism enzyme is substantially inactivated by substantially inactivating at least one gene encoding a drug metabolism enzyme. ### Claim 3 (depends on 2) The immunodeficient non-human animal according to claim 2, wherein the at least one endogenous gene encodes an enzyme of the endogenous cytochrome P450 monooxygenase system. ### Claim 4 (depends on 2) The immunodeficient non-human animal according to claim 2, wherein the at least one endogenous gene encodes any one or more genes comprised in the Cyp1a, Cyp2c, Cyp2d, or Cyp3a gene subfamilies. ### Claim 5 (depends on 4) The immunodeficient non-human animal according to claim 4, wherein the at least one endogenous gene encodes any one or more of Cyp1a1, Cyp1a2, Cyp2c55, Cyp2c65, Cyp2c66, Cyp2c29, Cyp2c38, Cyp2c39, Cyp2c67, Cyp2c68, Cyp2c40, Cyp2c69, Cyp2c37, Cyp2c44, Cyp2c54, Cyp2c50, Cyp2c70, Cyp2c6, Cyp2c6, Cyp2c7, Cyp2c11, Cyp2c12, Cyp2c13, Cyp2c22, Cyp2c23, Cyp2c24, Cyp2c79, Cyp2c80, Cyp2d1, Cyp2d2, Cyp2d3, Cyp2d4, Cyp2d5 Cyp2d22, Cyp2d11, Cyp2d10, Cyp2d9, Cyp2d12, Cyp2d34, Cyp2d13, Cyp2d40, Cyp2d26, Cyp3a1, Cyp3a2, Cyp3a9, Cyp3a18, Cyp3a23, Cyp3a62, Cyp3a73, Cyp3a13, Cyp3a11, Cyp3a16, Cyp3a25, Cyp3a41, Cyp3a44, Cyp3a57, Cyp3a58-ps, Cyp3a59 or functionally equivalent orthologues and homologues. ### Claim 6 (depends on 1) The immunodeficient non-human animal according to claim 1, wherein genes encoding endogenous transcription factors Car or Pxr are substantially inactivated, optionally wherein both Car and Pxr are substantially inactivated. ### Claim 7 (depends on 6) The immunodeficient non-human animal according to claim 6, wherein the Cyp1a, Cyp2c, Cyp2d, and Cyp3a gene subfamilies and Pxr and Car are substantially inactivated. ### Claim 8 (depends on 6) The immunodeficient non-human animal according to claim 6, wherein Cyp1a1, Cyp1a2, Cyp2c29, Cyp2c37, Cyp2c38, Cyp2c39, Cyp2c40, Cyp2c44, Cyp2c50, Cyp2c54, Cyp2c55, Cyp2c65, Cyp2c66, Cyp2c67, Cyp2c68, Cyp2c69, Cyp2c70, Cyp2d9, Cyp2d10, Cyp2d11, Cyp2d12, Cyp2d13, Cyp2d22, Cyp2d26, Cyp2d34, Cyp2d40, Cyp3a11, Cyp3a13, Cyp3a16, Cyp3a25, Cyp3a41, Cyp3a44, Cyp3a57, Cyp3a59 and Pxr and Car are substantially inactivated. ### Claim 9 (depends on 6) The immunodeficient non-human animal according to claim 6, wherein Cyp1a1, Cyp1a2, Cyp2a2, Cyp2a3, Cyp2b2, Cyp2b3, Cyp2b12, Cyp2b15, Cyp2b21, Cyp2b31, Cyp2c6, Cyp2c6, Cyp2c7, Cyp2c11, Cyp2c12, Cyp2c13, Cyp2c22, Cyp2c23, Cyp2c24, Cyp2c79, Cyp2c80, Cyp2c81, Cyp2c68, Cyp2c69, Cyp2c70, Cyp2d1, Cyp2d2, Cyp2d3, Cyp2d4, Cyp2d5, Cyp3a1, Cyp3a2, Cyp3a9, Cyp3a18, Cyp3a23, Cyp3a62, Cyp3a73, Cyp4a1, Cyp4a2, Cyp4a3, Cyp4a8 and Pxr and Car are substantially inactivated. ### Claim 10 (depends on 1) The immunodeficient non-human animal according to claim 1, wherein any one or more human genes selected from the list comprising: CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2A7, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1, CYP3A4, CYP3A5, CYP3A7, CYP3A43, CYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, or CYP4Z1, or any functional equivalents thereof are expressed in the immunodeficient non-human animal ### Claim 11 (depends on 10) The immunodeficient non-human animal according to claim 10, wherein human CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4 and CYP3A7, or any functional equivalents thereof are expressed in the immunodeficient non-human animal. ### Claim 12 (depends on 1) The immunodeficient non-human animal according to claim 1, wherein human CAR and/or PXR are expressed in the immunodeficient non-human animal. ### Claim 13 (depends on 1) The immunodeficient non-human animal according to claim 1, wherein the endogenous Cyp1a, Cyp2c, Cyp2d, and Cyp3a gene subfamilies and Pxr and Car are substantially inactivated, and human CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4, CYP3A7, CAR and PXR are expressed the immunodeficient non-human animal. ### Claim 14 (depends on 1) The immunodeficient non-human animal according to claim 1, wherein the endogenous recombination activating gene 2 (Rag2) is substantially inactivated. ### Claim 15 (depends on 1) The immunodeficient non-human animal according to claim 1, wherein the immunodeficient non-human animal lacks functional T, B and/or NK cells. ### Claim 16 (depends on 1) The immunodeficient non-human animal according to claim 1, wherein the immunodeficient non-human animal is heterozygous for the endogenous Cyp2c subfamily gene cluster expression, wherein one allele of the endogenous Cyp2c subfamily gene cluster is substantially active. ### Claim 17 (depends on 16) The immunodeficient non-human animal according to claim 16, wherein the animal is female. ### Claim 18 (depends on 1) The immunodeficient non-human animal according to claim 1, wherein the immunodeficient non-human animal is an embryo, a neonate or an adult. ### Claim 19 (depends on 1) A cell isolated from an immunodeficient non-human animal according to claim 1. ### Claim 20 (depends on 19) The cell according to claim 19, wherein the cell is a germ cell or a somatic cell. ### Claim 21 (depends on 19) A method of performing ex vivo or in vitro drug studies, wherein the method comprises: (i) providing a cell according to claim 19; optionally wherein the cell is maintained in cell culture; (ii) administering to the cell at least one test compound; and (iii) analysing at least one cellular characteristic. ### Claim 22 (depends on 1) A method of generating an immunodeficient non-human animal according to claim 1, wherein the method comprises substantially inactivating at least one endogenous drug metabolism enzyme in the immunodeficient non-human animal. ### Claim 23 (depends on 22) The method according to claim 22, wherein the method comprises substantially inactivating at least one or more endogenous drug metabolism enzymes from the list comprising: Cyp1a1, Cyp1a2, Cyp2c55, Cyp2c65, Cyp2c66, Cyp2c29, Cyp2c38, Cyp2c39, Cyp2c67, Cyp2c68, Cyp2c40, Cyp2c69, Cyp2c37, Cyp2c44, Cyp2c54, Cyp2c50, Cyp2c70, Cyp2c6, Cyp2c6, Cyp2c7, Cyp2c11, Cyp2c12, Cyp2c13, Cyp2c22, Cyp2c23, Cyp2c24, Cyp2c79, Cyp2c80, Cyp2d1, Cyp2d2, Cyp2d3, Cyp2d4, Cyp2d5 Cyp2d22, Cyp2d11, Cyp2d10, Cyp2d9, Cyp2d12, Cyp2d34, Cyp2d13, Cyp2d40, Cyp2d26, Cyp3a1, Cyp3a2, Cyp3a9, Cyp3a18, Cyp3a23, Cyp3a62, Cyp3a73, Cyp3a13, Cyp3a11, Cyp3a16, Cyp3a25, Cyp3a41, Cyp3a44, Cyp3a57, Cyp3a58-ps, and Cyp3a59 or functionally equivalent orthologues and homologues. ### Claim 24 (depends on 22) The method according to claim 22, wherein the method comprises substantially inactivating endogenous transcription factors Car and/or Pxr, preferably both endogenous Car and Pxr are substantially inactivated. ### Claim 25 (depends on 22) The method according to claim 22, wherein the method comprises substantially inactivating Cyp1a1, Cyp1a2, Cyp2c29, Cyp2c37, Cyp2c38, Cyp2c39, Cyp2c40, Cyp2c44, Cyp2c50, Cyp2c54, Cyp2c55, Cyp2c65, Cyp2c66, Cyp2c67, Cyp2c68, Cyp2c69, Cyp2c70, Cyp2d9, Cyp2d10, Cyp2d11, Cyp2d12, Cyp2d13, Cyp2d22, Cyp2d26, Cyp2d34, Cyp2d40, Cyp3a11, Cyp3a13, Cyp3a16, Cyp3a25, Cyp3a41, Cyp3a44, Cyp3a57, Cyp3a59 and Pxr and Car in the immunodeficient non-human animal. ### Claim 26 (depends on 22) The method according to claim 22, wherein the method comprises substantially inactivating Cyp1a1, Cyp1a2, Cyp2a2, Cyp2a3, Cyp2b2, Cyp2b3, Cyp2b12, Cyp2b15, Cyp2b21, Cyp2b31, Cyp2c6, Cyp2c6, Cyp2c7, Cyp2c11, Cyp2c12, Cyp2c13, Cyp2c22, Cyp2c23, Cyp2c24, Cyp2c79, Cyp2c80, Cyp2c81, Cyp2c68, Cyp2c69, Cyp2c70, Cyp2d1, Cyp2d2, Cyp2d3, Cyp2d4, Cyp2d5, Cyp3a1, Cyp3a2, Cyp3a9, Cyp3a18, Cyp3a23, Cyp3a62, Cyp3a73, Cyp4a1, Cyp4a2, Cyp4a3, Cyp4a8 and Pxr and Car, in the immunodeficient non-human animal. ### Claim 27 (depends on 22) The method of claim 22, wherein the method further comprises introducing at least one DNA sequence encoding at least one human drug metabolising enzyme in the immunodeficient non-human animal. ### Claim 28 (depends on 27) The method according to claim 27, wherein the method further comprises introducing a plurality of DNA sequences encoding a plurality of human drug metabolising enzymes into the immunodeficient non-human animal. ### Claim 29 (depends on 27) The method according to claim 27, wherein the at least one DNA sequence encoding a human drug metabolism enzyme, encodes at least one or more of the following human drug metabolism enzymes: CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2A7, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1, CYP3A4, CYP3A5, CYP3A7, CYP3A43, CYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, or CYP4Z1, or any functional equivalents thereof. ### Claim 30 (depends on 27) The method according to claim 27, wherein the method further comprises introducing at least one DNA sequence encoding human CAR or PXR, preferably both CAR and PXR. ### Claim 31 (depends on 22) The method according to claim 22, wherein the method comprises; (i) substantially inactivating the endogenous gene clusters Cyp1a, Cyp2c, Cyp2d, and Cyp3a and endogenous Car and Pxr in the immunodeficient non-human animal; (ii) introducing a plurality of DNA sequences encoding human CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4, CYP3A7, PXR and CAR in the immunodeficient non-human animal. ### Claim 32 (depends on 1) A method of performing preclinical drug studies, wherein the method comprises: (i) providing an immunodeficient non-human animal according to claim 1; (ii) administering at least one test compound to the animal; (iii) obtaining at least one biological sample from the animal, and/or recording clinical parameters of the animal; and where at least one biological sample has been obtained, (iv) analysing the biological sample for at least one analyte. ### Claim 33 (depends on 1) A method of measuring rate of metabolism of a drug compound, wherein the method comprises: (i) providing an immunodeficient non-human animal according to claim 1; (ii) administering at least one test compound to the animal; (iii) obtaining at least one biological sample from the animal, and/or recording clinical parameters of the animal; and where at least one biological sample has been obtained, (iv) measuring the measuring the rate of metabolism of the compound in the biological sample. ### Claim 34 (depends on 32) The method according to claim 32, wherein the method comprises a further step of transplanting human cells into the immunodeficient non-human animal prior to performing step (ii). ### Claim 35 (depends on 34) The method according to claim 34, wherein the human cells are patient-derived cells, healthy donor cells or a cell line. ### Claim 36 (depends on 35) The method according to claim 35, wherein patient-derived cells are cancer cells. ### Claim 37 (depends on 1) A method of testing one or more pharmaceutical compounds, wherein the method comprises: (i) providing an immunodeficient non-human animal according to claim 1; (ii) administering at least one test compound to the animal; and (iii) obtaining at least one biological sample from the animal, and/or recording clinical parameters of the animal; and optionally, where at least one biological sample has been obtained, (iv) analysing the biological sample for at least one analyte or clinical parameter. ### Claim 38 (depends on 1) A method of testing anti-cancer compounds, wherein the method comprises: (i) providing an immunodeficient non-human animal according to claim 1; (ii) transplanting healthy and/or cancerous human cells into the animal; (iii) obtaining at least one biological sample from the animal, and/or recording clinical parameters of the animal; and where at least one biological sample has been obtained, (iv) analysing the biological sample for at least one analyte or clinical parameter. ### Claim 39 (depends on 1) A method of testing anti-malarial compounds, wherein the method comprises: (i) providing an immunodeficient non-human animal according to claim 1; (ii) infecting the animal with a Plasmodium parasite; (iii) obtaining at least one biological sample from the animal, and/or optionally recording clinical parameters of the animal; and where at least one biological sample has been obtained, (iv) analysing the biological sample for at least one analyte or clinical parameter. ### Claim 40 (depends on 37) The method according to claim 37, wherein the method comprises a further step of transplanting human cells into the immunodeficient non-human animal prior to, or simultaneously to, or immediately after, performing step (ii) of the method. ### Claim 41 (depends on 39) The method according to claim 39, wherein the Plasmodium parasite is any one of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, or Plasmodium knowlesi.