title: The AAV-mediated and RNA-guided CRISPR/Cas9 system for gene therapy of DMD and BMD.
abstract: Mutations in the dystrophin gene (Dmd) result in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), which afflict many newborn boys. In 2016, Brain and Development published several interesting articles on DMD treatment with antisense oligonucleotide, kinase inhibitor, and prednisolone. Even more strikingly, three articles in the issue 6271 of Science in 2016 provide new insights into gene therapy of DMD and BMD via the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). In brief, adeno-associated virus (AAV) vectors transport guided RNAs (gRNAs) and Cas9 into mdx mouse model, gRNAs recognize the mutated Dmd exon 23 (having a stop codon), and Cas9 cut the mutated exon 23 off the Dmd gene. These manipulations restored expression of truncated but partially functional dystrophin, improved skeletal and cardiac muscle function, and increased survival of mdx mice significantly. This review concisely summarized the related advancements and discussed their primary implications in the future gene therapy of DMD, including AAV-vector selection, gRNA designing, Cas9 optimization, dystrophin-restoration efficiency, administration routes, and systemic and long-term therapeutic efficacy. Future orientations, including off-target effects, safety concerns, immune responses, precision medicine, and Dmd-editing in the brain (potentially blocked by the blood-brain barrier) were also elucidated briefly. Collectively, the AAV-mediated and RNA-guided CRISPR/Cas9 system has major superiorities compared with traditional gene therapy, and might contribute to the treatment of DMD and BMD substantially in the near future.
authors.affiliation: College of Medicine, Affiliated Hospital, Hebei University of Engineering, Handan 056002, PR China. Electronic address: wangjingzhang1981@gmail.com.
authors.forename: Jing-Zhang
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: Department of Social Science, Hebei University of Engineering, Handan 056038, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.affiliation: College of Medicine, Affiliated Hospital, Hebei University of Engineering, Handan 056002, PR China.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Shi
authors.affiliation: College of Medicine, Affiliated Hospital, Hebei University of Engineering, Handan 056002, PR China.
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Xu
authors.affiliation: College of Medicine, Affiliated Hospital, Hebei University of Engineering, Handan 056002, PR China. Electronic address: gdyylzj@163.com.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D064113:CRISPR-Cas Systems; D000229:Dependovirus / Q000235:genetics; D016189:Dystrophin / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000628:therapy*
chemical_list: D016189:Dystrophin
keywords: Adeno-associated virus vector; Becker muscular dystrophy; CRISPR/Cas9; Duchenne muscular dystrophy; Dystrophin; Gene therapy