Open Access
In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy
Christopher E. Nelson,Chady H. Hakim,David G. Ousterout,Pratiksha I. Thakore,Eirik A. Moreb,Ruth M. Castellanos Rivera,Sarina Madhavan,X. Pan,F. A. Ran,Winston X. Yan,Aravind Asokan,Feng Zhang,Dongsheng Duan,Charles A. Gersbach +13 more
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TLDR
This work establishes CRISPR-Cas9–based genome editing as a potential therapy to treat DMD and partially restored dystrophin protein expression in skeletal and cardiac muscle and improved skeletal muscle function.Abstract:
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. Duchenne muscular dystrophy (DMD) is a devastating disease affecting about 1 out of 5000 male births and caused by mutations in the dystrophin gene. Genome editing has the potential to restore expression of a modified dystrophin gene from the native locus to modulate disease progression. In this study, adeno-associated virus was used to deliver the clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 system to the mdx mouse model of DMD to remove the mutated exon 23 from the dystrophin gene. This includes local and systemic delivery to adult mice and systemic delivery to neonatal mice. Exon 23 deletion by CRISPR-Cas9 resulted in expression of the modified dystrophin gene, partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle, improvement of muscle biochemistry, and significant enhancement of muscle force. This work establishes CRISPR-Cas9–based genome editing as a potential therapy to treat DMD.read more
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Journal ArticleDOI
Adeno-associated virus vector as a platform for gene therapy delivery
TL;DR: The fundamentals of AAV and vectorology are discussed, focusing on current therapeutic strategies, clinical progress and ongoing challenges.
Journal ArticleDOI
CRISPR-Based Technologies for the Manipulation of Eukaryotic Genomes.
Alexis C. Komor,Alexis C. Komor,Alexis C. Komor,Ahmed H. Badran,Ahmed H. Badran,Ahmed H. Badran,David R. Liu,David R. Liu,David R. Liu +8 more
TL;DR: Recent developments that extend the generality, DNA specificity, product selectivity, and fundamental capabilities of natural CRISPR systems are described.
Journal ArticleDOI
Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects
TL;DR: Recent advances of the three major genome editing technologies are reviewed and the applications of their derivative reagents as gene editing tools in various human diseases and potential future therapies are discussed, focusing on eukaryotic cells and animal models.
Therapeutic genome editing: prospects and challenges
TL;DR: Current progress toward developing programmable nuclease–based therapies as well as future prospects and challenges are discussed.
Journal ArticleDOI
Gene therapy comes of age.
Cynthia E. Dunbar,Katherine A. High,J. Keith Joung,Donald B. Kohn,Keiya Ozawa,Michel Sadelain +5 more
TL;DR: The pioneering work that led the gene therapy field to its current state is reviewed, gene-editing technologies that are expected to play a major role in the field's future are described, and practical challenges in getting these therapies to patients who need them are discussed.
References
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Martin Jinek,Krzysztof Chylinski,Krzysztof Chylinski,Ines Fonfara,Michael H. Hauer,Jennifer A. Doudna,Emmanuelle Charpentier +6 more
TL;DR: This study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing.
Multiplex Genome Engineering Using CRISPR/Cas Systems
Le Cong,F. A. Ran,David Benjamin Turitz Cox,Shuailiang Lin,Robert P. J. Barretto,Naomi Habib,Patrick D. Hsu,Xuebing Wu,Wenyan Jiang,Luciano A. Marraffini,Feng Zhang +10 more
TL;DR: Two different type II CRISPR/Cas systems are engineered and it is demonstrated that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.
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RNA-Guided Human Genome Engineering via Cas9
Prashant Mali,Luhan Yang,Kevin M. Esvelt,John Aach,Marc Güell,James E. DiCarlo,Julie E. Norville,George M. Church,George M. Church +8 more
TL;DR: The type II bacterial CRISPR system is engineer to function with custom guide RNA (gRNA) in human cells to establish an RNA-guided editing tool for facile, robust, and multiplexable human genome engineering.
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Dystrophin: The protein product of the duchenne muscular dystrophy locus
TL;DR: The identification of the mdx mouse as an animal model for DMD has important implications with regard to the etiology of the lethal DMD phenotype, and the protein dystrophin is named because of its identification via the isolation of the Duchenne muscular dystrophy locus.
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RNA-programmed genome editing in human cells
TL;DR: It is shown here that Cas9 assembles with hybrid guide RNAs in human cells and can induce the formation of double-strand DNA breaks at a site complementary to the guide RNA sequence in genomic DNA.