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Mutant fus model for als

A mutant type, FUS-R521 technology, applied in the field of ALS model construction, can solve the problems of genome integrity damage, uncertain genome insertion site, unstable copy number, etc., achieve stable copy number and avoid non-directed mutation

Active Publication Date: 2020-02-07
神济昌华(北京)生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, transgenic strategies have other considerations, including uncertain genomic insertion sites, unstable copy number, potential disruption of genomic integrity, ectopic expression patterns driven by exogenous promoters, and lack of endogenous regulation of splicing

Method used

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  • Mutant fus model for als
  • Mutant fus model for als
  • Mutant fus model for als

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Experimental program
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Effect test

Embodiment

[0089] Generation of the mFUS-R513C mouse model of ALS

[0090] The inventors employed a CRISPR-Cas9-based knock-in (KI) approach. They chose hFUS-R521C to generate the KIALS mouse model for three reasons. First, the R521C mutation is located at the C-terminus of FUS, which is an atypical PY nuclear localization signal (NLS), where more than half of the ALS-associated FUS mutations are gathered. Among these mutations, R521C was the most common mutation, accounting for 30% of the total. Second, the R521C mutation has been identified in familial sporadic ALS patients with high disease incidence. Third, the FUS R521C transgenic mouse and rat models exhibit strong features of ALS-like lesions.

[0091] To generate the KI mouse strain, the inventors first analyzed the conservation of the FUS protein across species ( figure 1 A). The C-terminal NLS encoded by the last exon of mouse FUS is similar to human (515GEHRQD R RERPY526) has the same C-terminal NLS. The mouse equivalen...

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Abstract

An ALS model, a method for screening a medicament for treating ALS and a method for constructing ALS model, wherein the ALS model expresses mutant FUS and the mutant FUS is FUS-R521C.

Description

technical field [0001] Embodiments of the present disclosure relate generally to biomedicine, and more particularly, to an ALS model, a method of screening drugs for treating ALS, and a method of constructing an ALS model. Background technique [0002] Emerging evidence suggests that abnormalities in RNA metabolism, including RBP gain-of-function, loss of RNA helicase function, and misprocessing of pre-mRNA splicing, contribute to neurodegenerative diseases. Among them, mutations in genes encoding two structurally similar RBPs (TDP-43 and FUS) were associated with ALS and FTD, two neurodegenerative diseases with genetic and pathological overlap. More strikingly, ubiquitin-positive and mislocalized TDP-43 and FUS were found in a large proportion of ALS and FTD, although many of them did not carry these two RBP mutations, highlighting the role of RBP dysfunction in pathogenesis key role in. However, the disease mechanisms of neurodegenerative diseases caused by dysfunction o...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/10A01K67/027C12Q1/02A61K49/00
CPCA01K67/0278A01K2217/072A01K2227/105A01K2267/0356A61P21/00C12N15/907C07K14/47C07K14/4702G01N33/6893G01N2800/2835G01N33/5058G01N33/5088C12N2310/20
Inventor 张雪贾怡昌
Owner 神济昌华(北京)生物科技有限公司