In vivo gene editing in dystrophic mouse muscle and muscle stem cells
By Mohammadsharif Tabebordbar, Kexian Zhu, Jason K. W. Cheng, W. Chew, J. Widrick, C. Maesner, Elizabeth Y Wu, Ru Xiao, F. Ran, L. Vandenberghe and 5 more. Science, 2015
989 citations recorded by the source corpus.
Editing can help build stronger muscles Much of the controversy surrounding the gene-editing technology called CRISPR/Cas9 centers on the ethics of germline editing of human embryos to correct disease-causing mutations. For certain disorders such as muscular dystrophy, it may be possible to achieve therapeutic benefit by editing the faulty gene in somatic cells. In proof-of-concept studies, Long et al., Nelson et al., and Tabebordbar et al. used adeno-associated virus-9 to deliver the CRISPR/Cas9 gene-editing system to young mice with a mutation in the gene coding for dystrophin, a muscle protein deficient in patients with Duchenne muscular dystrophy. Gene editing partially restored dystrophin protein expression in skeletal and cardiac muscle and improved skeletal muscle function. Science, this issue p. 400, p. 403, p. 407 Gene editing via CRISPR-Cas9 restores dystrophin protein and improves muscle function in mouse models of muscular dystrophy. Frame-disrupting mutations in the DMD gene, encoding dystrophin, compromise myofiber integrity and drive muscle deterioration in Duchenne muscular dystrophy (DMD). Removing one or more exons from the mutated transcript can produce an in-frame mRNA and a truncated, but still functional, protein. In this study, we developed and tested a direct gene-editing approach to induce exon deletion and recover dystrophin expression in the mdx mouse model of DMD. Delivery by adeno-associated virus (AAV) of clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 endonucleases coupled with paired guide RNAs flanking the mutated Dmd exon23 resulted in excision of intervening DNA and restored the Dmd reading frame in myofibers, cardiomyocytes, and muscle stem cells after local or systemic delivery. AAV-Dmd CRISPR treatment partially recovered muscle functional deficiencies and generated a pool of endogenously corrected myogenic precursors in mdx mouse muscle.
Subfields: Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/f5654881a5f20f8daac7890ec227df7afae80716
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In Molecular Biology
Citations in the corpus
- Engineering the Delivery System for CRISPR-based Genome Editing (2018, background): “The most common viral vector used for Cas9 delivery is the adeno-associated virus (AAV) vector [14, 28, 29].”
- Delivering CRISPR: a review of the challenges and approaches (2018, methodology): “Groups have used of SaCas9 in AAV vectors to target the cholesterol regulatory gene Pcsk9 (Ran et al., 2015) and disrupt mutations in the DMD gene in adult mice (Nelson et al., 2016; Tabebordbar et al., 2016).”
- Identification of Pre-Existing Adaptive Immunity to Cas9 Proteins in Humans (2018, positive): “Much of the effort to treat disease in vivo has used Cas9 delivery systems that express the Cas9 protein for prolonged periods of time, such as through a non-integrating AAV vector or even through nanoparticle delivery of mRNA to non-dividing hepatocytes (8, 10-12).”