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Non-human animals comprising slc30a8 mutation and methods of use

A non-human animal, endogenous technology, applied in several S domains, can solve the problem of incomplete recapitulation of protective human phenotypes

Active Publication Date: 2020-08-21
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Several Slc30a8 knockout mouse strains have been identified, but they do not fully recapitulate the protective human phenotype

Method used

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  • Non-human animals comprising slc30a8 mutation and methods of use
  • Non-human animals comprising slc30a8 mutation and methods of use
  • Non-human animals comprising slc30a8 mutation and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] Example 1. Generation of mice comprising a mutated Slc30a8 locus

[0169] To generate a mouse model carrying the allele corresponding to the putative human SLC30A8 LOF allele (c.412C>T (transcript accession number NM_173851.2), p.Arg138X), a mutant mouse Slc30a8 allele was generated Gene (c.409C>T (transcript accession number NM_172816.3), p.Arg137X). Table 3 provides information on the mouse Slc30a8 and human SLC30A8 genes. Figure 11 An alignment of human SLC30A8 and mouse SLC30A8 proteins is shown. The mutant allele has a dC to dT substitution at the mouse Slc30a8 codon encoding R137 in exon 3 (c.409C>T), changing the codon from CGA to TGA (p.Arg137X), resulting in the expected A stop codon that would result in a truncated protein. The mutant allele also has a self-deleting neomycin selection cassette flanked by loxP sites inserted at intron 3 (loxP-mPrm1-Crei-hUb1-em7-Neo-pA-loxP cassette (4,810 bp)), deleted the 29bp endogenous intronic sequence. The endogenou...

Embodiment 2

[0179] Example 2: Characterization of SLC30A8 R138X mice.

[0180] summary

[0181] SLC30A8 encodes a zinc transporter that is mainly expressed in islets of the pancreas. In beta cells, it transports zinc into insulin-containing secretory granules. Loss-of-function (LOF) mutations in SLC30A8 protect against type 2 diabetes in humans. Several Slc30a8 knockout mouse strains have been characterized, but the human phenotype cannot be fully recapitulated. Indeed, Slc30a8-deficient mice had reduced plasma insulin levels and impaired glucose tolerance, a phenotype that we reproduce here in control Slc30a8-deficient mice. We generated a knock-in mouse model with a mutation in the mouse Slc30a8 locus (c.409C>T (transcript accession number NM_172816.3), p.Arg137X) that corresponds to the human SLC30A8 putative LOF mutation R138X . Although the mutation in the mouse Slc30a8 gene is in the codon encoding amino acid residue 137 of the mouse SLC30A8 protein, these mice are referred to ...

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Abstract

Non-human animal genomes, non-human animal cells, and non-human animals comprising a mutated Slc30a8 locus and methods of making and using such non-human animal genomes, non-human animal cells, and non-human animals are provided. The non-human animals can have increased insulin secretory capacity.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Application No. 62 / 584,288, filed November 10, 2017, U.S. Application No. 62 / 666,337, filed May 3, 2018, and U.S. Application No. 62 / 689,945, each of which is hereby incorporated by reference in its entirety for all purposes. [0003] References to Sequence Listings submitted as text files via EFS Web [0004] The sequence listing written in file 523060SEQLIST.txt is 39.2 KB, created on November 5, 2018, and is incorporated by reference. Background technique [0005] Diabetes mellitus is a disease characterized by metabolic defects in insulin-responsive tissues and insulin-producing pancreatic beta cells, resulting in an inability to maintain proper blood sugar levels in the body. Diabetes mellitus in humans can be defined as a disease corresponding to a fasting blood glucose concentration of greater than 125 mg / dL or a plasma glucose concentration of greater than 199 mg / dL two hours af...

Claims

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Application Information

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IPC IPC(8): A01K67/027C07K14/47
CPCA01K67/0278C07K14/47A01K2217/072A01K2227/105A01K2267/0362A01K67/0275A01K2207/25A01K2217/05A01K2217/077A01K2217/206C12N15/902
Inventor 桑德拉·克莱纳约瑟·F·罗哈斯杰斯珀·格罗马达
Owner REGENERON PHARM INC
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