# US 10,765,762 B2 · Humanized model of kidney and liver disorders > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,765,762 B2 - Document ID: US10765762B2 - Status: Granted - Kind: B2 - Application number: 15/904,808 - Filed: 2018-02-26 - Published: 2018-08-30 - Granted: 2020-09-08 - Earliest claimed: 2017-02-27 - Assignees: Regeneron Pharmaceuticals, Inc. - Applicants: Regeneron Pharmaceuticals, Inc. - Inventors: Kishor Devalaraja-Narashimha; Lori Morton; Yifan Luo; Cong Huang; Karolina Meagher; Sarah Casanova - Web page: https://patentgrep.com/patent/US10765762B2 ## CPC - A61K 49/0008: {Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure} - A01K 67/0278: Knock-in vertebrates, e.g. humanised vertebrates - A61P 13/12: of the kidneys - C07K 14/472: {Complement proteins, e.g. anaphylatoxin, C3a, C5a} - C07K 16/18: against material from animals or humans - 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)} - G01N 33/5088: {of vertebrates} - A01K 2217/072: maintaining or altering function, i.e. knock in - A01K 2227/105: Murine - A01K 2267/0368: Animal model for inflammation - A61K 2039/505: {comprising antibodies} - 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) - 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 - 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 Provided herein, inter alia, are non-human animals comprising nucleic acid sequences encoding a C3 protein that comprises a human sequence as well as transgenic non-human animals comprising a C3 gene that is human in whole or in part as well as methods for using the same to screen for candidate therapeutic molecules to treat complement-related nephropathies. Also provided herein are methods for improving kidney function in an individual diagnosed with or thought to have a complement-related nephropathy. ## Claims ### Claim 1 A method for assessing the in vivo therapeutic efficacy of an agent for use in a treatment of a complement-related nephropathy, the method comprising: (a) administering the agent to a mouse whose genome comprises a replacement at an endogenous mouse C3 locus to form a modified C3 gene, wherein the replacement is (i) a replacement of a mouse gene sequence comprising exon 1 through exon 41 of the mouse C3 gene with a nucleic acid sequence comprising exon 1 through exon 41 of the human C3 ene, or (ii) a replacement of a mouse gene sequence comprising exon 2 through exon 41 of the mouse C3 gene with a nucleic acid sequence comprising exon 2 through exon 41 of the human C3 gene, wherein expression of the modified C3 gene is under control of mouse regulatory elements at the endogenous mouse C3 locus, wherein the mouse spontaneously exhibits one or more symptoms of the complement-related nephropathy; and (b) measuring the one or more symptoms of the complement-related nephropathy in the mouse, and categorizing the agent as a therapeutic agent for treating the complement-related nephropathy when the agent inhibits the one or more symptoms of the nephropathy compared to control mice who have not been administered the agent, wherein the one or more symptoms of the nephropathy are selected from the group consisting of (i) one or more of glomerulonephritis, basophilic tubules, sclerotic glomeruli, dilated tubules with protein casts, mesangial matrix expansion, glomerular hypertrophy, mononuclear interstitial inflammation, (ii) C3 protein deposition in the kidney, (iii) deposition of C5b-9 membrane attack complexes in the kidney, (iv) one or more of elevated blood urea nitrogen (BUN), serum lipase, serum cystatin C, or serum non-high density lipoproteins, and (v) increased urinary albumin or C5a. ### Claim 2 (depends on 1) The method of claim 1, wherein the mouse is incapable of expressing a mouse C3 protein. ### Claim 3 (depends on 2) The method of claim 2, wherein the mouse expresses a mouse C5 protein encoded by an endogenous mouse C5 gene. ### Claim 4 (depends on 1) The method of claim 1, wherein the agent is selected from the group consisting of small molecule chemical compounds, peptides and antibodies. ### Claim 5 (depends on 4) The method of claim 4, wherein the agent is an antibody. ### Claim 6 (depends on 1) The method of claim 1, wherein the agent is an inhibitory nucleic acid. ### Claim 7 (depends on 1) The method of claim 1, wherein the one or more symptoms of the nephropathy are selected from one or more of the group consisting of glomerulonephritis, basophilic tubules, sclerotic glomeruli, dilated tubules with protein casts, mesangial matrix expansion, glomerular hypertrophy, and mononuclear interstitial inflammation. ### Claim 8 (depends on 1) The method of claim 1, wherein the one or more symptoms of the nephropathy comprise C3 protein deposition in the kidney. ### Claim 9 (depends on 1) The method of claim 1, wherein the one or more symptoms of the nephropathy comprise deposition of C5b-9 membrane attack complexes in the kidney. ### Claim 10 (depends on 1) The method of claim 1, wherein the one or more symptoms of the nephropathy comprise one or more of elevated blood urea nitrogen (BUN), serum lipase, serum cystatin C, or serum non-high density lipoproteins. ### Claim 11 (depends on 1) The method of claim 1, wherein the one or more symptoms of the nephropathy comprise increased urinary albumin or C5a. ### Claim 12 A method for assessing the in vivo therapeutic efficacy of an agent for use in a treatment for fibrosis of the liver, the method comprising: (a) administering the agent to a mouse which comprises a replacement at an endogenous mouse C3 locus to form a modified C3 gene, wherein the replacement is (i) a replacement of a mouse gene sequence comprising exon 1 through exon 41 of the mouse C3 gene with a nucleic acid sequence comprising exon 1 through exon 41 of the human C3 gene, or (ii) a replacement of a mouse gene sequence comprising exon 2 through exon 41 of the mouse C3 gene with a nucleic acid sequence comprising exon 2 through exon 41 of the human C3 gene wherein expression of the modified C3 gene is under control mouse regulatory elements at the endogenous mouse C3 locus, wherein the mouse spontaneously exhibits one or more symptoms of fibrosis of the liver; and (b) measuring the one or more symptoms of fibrosis of the liver in the mouse and categorizing the agent as a therapeutic agent for treating fibrosis of the liver when the agent inhibits the one or more symptoms of fibrosis of the liver compared to control mice who have not been administered the agent. ### Claim 13 (depends on 12) The method of claim 12, wherein the mouse is incapable of expressing a mouse C3 protein. ### Claim 14 (depends on 13) The method of claim 13, wherein the mouse expresses a mouse C5 protein encoded by an endogenous mouse C5 gene. ### Claim 15 (depends on 12) The method of claim 12, wherein the agent is selected from the group consisting of small molecule chemical compounds, peptides and antibodies. ### Claim 16 (depends on 12) The method of claim 12, wherein the agent is an inhibitory nucleic acid.