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Curated Papers > Highly Cited Authoritative Literature on "CRISPR Gene Editing"

Correction of muscular dystrophies by CRISPR gene editing. ​

Literature Information ​

PMID32478678
JournalThe Journal of clinical investigation
Impact Factor13.6
JCR QuartileQ1
Publication Year2020
Times Cited55
KeywordsMuscular Dystrophies, CRISPR Gene Editing, Genomic Correction
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN0021-9738
Pages2766-2776
Issue130(6)
AuthorsFrancesco Chemello, Rhonda Bassel-Duby, Eric N Olson

TL;DR ​

This review discusses the potential of genome editing technologies, particularly CRISPR/Cas9, to correct mutations responsible for muscular dystrophies, such as Duchenne muscular dystrophy, which have been successfully amended in various animal models and human cells. The research highlights the promise of a one-time treatment approach that could restore normal gene expression in long-lived muscle tissues, addressing a critical gap in the development of curative therapies for these debilitating disorders.

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Muscular Dystrophies · CRISPR Gene Editing · Genomic Correction

Abstract ​

Muscular dystrophies are debilitating disorders that result in progressive weakness and degeneration of skeletal muscle. Although the genetic mutations and clinical abnormalities of a variety of neuromuscular diseases are well known, no curative therapies have been developed to date. The advent of genome editing technology provides new opportunities to correct the underlying mutations responsible for many monogenic neuromuscular diseases. For example, Duchenne muscular dystrophy, which is caused by mutations in the dystrophin gene, has been successfully corrected in mice, dogs, and human cells through CRISPR/Cas9 editing. In this Review, we focus on the potential for, and challenges of, correcting muscular dystrophies by editing disease-causing mutations at the genomic level. Ideally, because muscle tissues are extremely long-lived, CRISPR technology could offer a one-time treatment for muscular dystrophies by correcting the culprit genomic mutations and enabling normal expression of the repaired gene.

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Primary Questions Addressed ​

  1. What are the specific challenges faced in the clinical application of CRISPR gene editing for treating muscular dystrophies?
  2. How does the success of CRISPR/Cas9 editing in animal models translate to potential therapies for human patients with muscular dystrophies?
  3. What are the ethical considerations surrounding the use of gene editing technologies like CRISPR in treating genetic disorders such as muscular dystrophies?
  4. How might advancements in CRISPR technology impact the development of treatments for other neuromuscular diseases beyond muscular dystrophies?
  5. What are the long-term implications of correcting muscular dystrophies at the genomic level for patient quality of life and disease management?

Key Findings ​

Research Background and Objectives ​

Muscular dystrophies are a group of genetic disorders characterized by progressive weakness and degeneration of skeletal muscle. Despite a thorough understanding of the genetic mutations and clinical manifestations associated with various neuromuscular diseases, effective curative therapies remain elusive. This review aims to explore the potential of genome editing technologies, particularly CRISPR/Cas9, to correct the genetic mutations responsible for these disorders, with a focus on Duchenne muscular dystrophy (DMD).

Main Methods/Materials/Experimental Design ​

The review primarily discusses the application of CRISPR/Cas9 genome editing in the context of muscular dystrophies. The methodology involves several key steps:

  1. Identification of Mutations: Recognizing specific genetic mutations in neuromuscular diseases, such as those in the dystrophin gene for DMD.
  2. CRISPR/Cas9 Design: Designing guide RNAs (gRNAs) that target the mutations for precise editing.
  3. Delivery Mechanisms: Employing various delivery systems to introduce the CRISPR components into muscle cells.
  4. Editing and Repair: Using CRISPR/Cas9 to induce double-strand breaks at the mutation sites, followed by cellular repair mechanisms to correct the mutations.

The following flowchart summarizes the technical approach:

Mermaid diagram

Key Results and Findings ​

  • Successful correction of mutations in animal models (mice and dogs) and human cells has been reported, demonstrating the feasibility of using CRISPR/Cas9 for gene therapy in muscular dystrophies.
  • The potential for a one-time treatment is highlighted, given the long-lived nature of muscle tissues, which could sustain the corrected gene expression over time.

Main Conclusions/Significance/Innovation ​

The review underscores the transformative potential of CRISPR/Cas9 genome editing as a viable therapeutic approach for muscular dystrophies. By addressing the root genetic causes, this technology could lead to significant advancements in treatment, moving towards the possibility of permanent cures rather than symptomatic management. The innovation lies in the ability to achieve precise genomic corrections that restore normal gene function.

Research Limitations and Future Directions ​

  • Limitations: The review acknowledges challenges such as off-target effects, efficiency of delivery methods, and the need for long-term studies to assess the durability of the gene edits.
  • Future Directions: It suggests further research into optimizing delivery systems, improving the precision of CRISPR technology, and exploring the ethical implications of genome editing in humans.
AspectDetails
Research FocusGenome editing in muscular dystrophies
Key TechnologyCRISPR/Cas9
Target ConditionDuchenne muscular dystrophy (DMD)
Main FindingSuccessful mutation correction in models
Therapeutic PotentialOne-time treatment with long-lasting effects
ChallengesOff-target effects, delivery efficiency, long-term outcomes
Future Research NeedsOptimize delivery, enhance precision, ethical considerations

References ​

  1. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. - Alexis C Komor;Yongjoo B Kim;Michael S Packer;John A Zuris;David R Liu - Nature (2016)
  2. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. - Jennifer A Doudna;Emmanuelle Charpentier - Science (New York, N.Y.) (2014)
  3. Multifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes. - Shayesteh R Ferdosi;Radwa Ewaisha;Farzaneh Moghadam;Sri Krishna;Jin G Park;Mo R Ebrahimkhani;Samira Kiani;Karen S Anderson - Nature communications (2019)
  4. In Vivo Genome Editing Restores Dystrophin Expression and Cardiac Function in Dystrophic Mice. - Mona El Refaey;Li Xu;Yandi Gao;Benjamin D Canan;T M Ayodele Adesanya;Sarah C Warner;Keiko Akagi;David E Symer;Peter J Mohler;Jianjie Ma;Paul M L Janssen;Renzhi Han - Circulation research (2017)
  5. The next generation of CRISPR-Cas technologies and applications. - Adrian Pickar-Oliver;Charles A Gersbach - Nature reviews. Molecular cell biology (2019)
  6. Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. - Christopher E Nelson;Yaoying Wu;Matthew P Gemberling;Matthew L Oliver;Matthew A Waller;Joel D Bohning;Jacqueline N Robinson-Hamm;Karen Bulaklak;Ruth M Castellanos Rivera;Joel H Collier;Aravind Asokan;Charles A Gersbach - Nature medicine (2019)
  7. Eteplirsen in the treatment of Duchenne muscular dystrophy. - Kenji Rowel Q Lim;Rika Maruyama;Toshifumi Yokota - Drug design, development and therapy (2017)
  8. CRISPR/Cas9-Induced (CTG⋅CAG)n Repeat Instability in the Myotonic Dystrophy Type 1 Locus: Implications for Therapeutic Genome Editing. - Ellen L van Agtmaal;Laurène M André;Marieke Willemse;Sarah A Cumming;Ingeborg D G van Kessel;Walther J A A van den Broek;Geneviève Gourdon;Denis Furling;Vincent Mouly;Darren G Monckton;Derick G Wansink;Bé Wieringa - Molecular therapy : the journal of the American Society of Gene Therapy (2017)
  9. In Situ Modification of Tissue Stem and Progenitor Cell Genomes. - Jill M Goldstein;Mohammadsharif Tabebordbar;Kexian Zhu;Leo D Wang;Kathleen A Messemer;Bryan Peacker;Sara Ashrafi Kakhki;Meryem Gonzalez-Celeiro;Yulia Shwartz;Jason K W Cheng;Ru Xiao;Trisha Barungi;Charles Albright;Ya-Chieh Hsu;Luk H Vandenberghe;Amy J Wagers - Cell reports (2019)
  10. High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. - Benjamin P Kleinstiver;Vikram Pattanayak;Michelle S Prew;Shengdar Q Tsai;Nhu T Nguyen;Zongli Zheng;J Keith Joung - Nature (2016)

Literatures Citing This Work ​

  1. Gene Editing Targeting the DUX4 Polyadenylation Signal: A Therapy for FSHD? - Romains Joubert;Virginie Mariot;Marine Charpentier;Jean Paul Concordet;Julie Dumonceaux - Journal of personalized medicine (2020)
  2. Transaminitis in a Three-year-old Boy with Duchenne Muscular Dystrophy. - Qiuli Xie;Yingen Feng;Jing Li;Xiaoqiao Chen;Jianqiang Ding - Journal of clinical and translational hepatology (2020)
  3. Duchenne muscular dystrophy. - Dongsheng Duan;Nathalie Goemans;Shin'ichi Takeda;Eugenio Mercuri;Annemieke Aartsma-Rus - Nature reviews. Disease primers (2021)
  4. Evaluation of CRISPR/Cas9 site-specific function and validation of sgRNA sequence by a Cas9/sgRNA-assisted reverse PCR technique. - Beibei Zhang;Jiamu Zhou;Miao Li;Yuanmeng Wei;Jiaojiao Wang;Yange Wang;Pingling Shi;Xiaoli Li;Zixu Huang;He Tang;Zongming Song - Analytical and bioanalytical chemistry (2021)
  5. Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy. - Fernanda Fortunato;Rachele Rossi;Maria Sofia Falzarano;Alessandra Ferlini - Journal of clinical medicine (2021)
  6. Precise correction of Duchenne muscular dystrophy exon deletion mutations by base and prime editing. - F Chemello;A C Chai;H Li;C Rodriguez-Caycedo;E Sanchez-Ortiz;A Atmanli;A A Mireault;N Liu;R Bassel-Duby;E N Olson - Science advances (2021)
  7. Single AAV-mediated CRISPR-Nme2Cas9 efficiently reduces mutant hTTR expression in a transgenic mouse model of transthyretin amyloidosis. - Jinkun Wen;Tianqi Cao;Jinni Wu;Yuxi Chen;Shengyao Zhi;Yanming Huang;Peilin Zhen;Guanglan Wu;Lars Aagaard;Jianxin Zhong;Puping Liang;Junjiu Huang - Molecular therapy : the journal of the American Society of Gene Therapy (2022)
  8. Toward the correction of muscular dystrophy by gene editing. - Eric N Olson - Proceedings of the National Academy of Sciences of the United States of America (2021)
  9. Towards precision medicine in heart failure. - Chad S Weldy;Euan A Ashley - Nature reviews. Cardiology (2021)
  10. Cardiac Myoediting Attenuates Cardiac Abnormalities in Human and Mouse Models of Duchenne Muscular Dystrophy. - Ayhan Atmanli;Andreas C Chai;Miao Cui;Zhaoning Wang;Takahiko Nishiyama;Rhonda Bassel-Duby;Eric N Olson - Circulation research (2021)

... (45 more literatures)

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