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Correction of muscular dystrophies by CRISPR gene editing. ​

文献信息 ​

PMID32478678
期刊The Journal of clinical investigation
影响因子13.6
JCR 分区Q1
发表年份2020
被引次数55
关键词肌肉萎缩症, CRISPR基因编辑, 基因组修复
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN0021-9738
页码2766-2776
期号130(6)
作者Francesco Chemello, Rhonda Bassel-Duby, Eric N Olson

一句话小结 ​

肌肉萎缩症是一类导致骨骼肌无力和退化的致残性疾病，目前尚无治愈方案。研究表明，基因组编辑技术（如CRISPR/Cas9）在纠正导致疾病的基因突变方面展现出巨大潜力，为肌肉萎缩症的治疗提供了新的希望。

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肌肉萎缩症 · CRISPR基因编辑 · 基因组修复

摘要 ​

肌肉萎缩症是一组致残性疾病，导致骨骼肌逐渐无力和退化。尽管各种神经肌肉疾病的遗传突变和临床异常已被广泛了解，但至今尚未开发出治愈疗法。基因组编辑技术的出现为纠正许多单基因神经肌肉疾病的根本突变提供了新机遇。例如，杜氏肌营养不良症是由于肌萎缩蛋白基因突变引起的，通过CRISPR/Cas9编辑技术，已成功在小鼠、狗和人类细胞中进行纠正。在本综述中，我们重点关注通过在基因组水平编辑导致疾病的突变来纠正肌肉萎缩症的潜力和挑战。理想情况下，由于肌肉组织的寿命极长，CRISPR技术可以通过纠正相关的基因组突变并使修复后的基因正常表达，提供对肌肉萎缩症的一次性治疗。

英文摘要 ​

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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主要研究问题 ​

  1. 除了Duchenne肌营养不良症，还有哪些其他类型的肌营养不良症可以通过CRISPR基因编辑进行治疗？
  2. CRISPR技术在纠正肌营养不良症时面临哪些主要技术挑战和伦理问题？
  3. 是否有临床试验正在进行，以评估CRISPR基因编辑在治疗肌营养不良症方面的有效性和安全性？
  4. CRISPR基因编辑对肌肉组织的长期影响是什么，是否存在潜在的副作用？
  5. 除了基因编辑，还有哪些其他治疗策略可以结合使用，以提高肌营养不良症的治疗效果？

核心洞察 ​

研究背景和目的 ​

肌肉萎缩症是一类导致骨骼肌逐渐无力和退化的严重疾病。尽管各种神经肌肉疾病的遗传突变和临床异常已被广泛了解，但迄今为止尚未开发出治愈性疗法。随着基因组编辑技术的发展，修正许多单基因神经肌肉疾病的基础突变提供了新的机会。本综述旨在探讨通过基因组水平编辑致病突变来纠正肌肉萎缩症的潜力及其面临的挑战。

主要方法/材料/实验设计 ​

本研究主要采用CRISPR/Cas9基因编辑技术，针对引起肌肉萎缩症的基因突变进行修正。以下是研究的技术路线图：

Mermaid diagram

关键结果和发现 ​

  1. 基因修正成功率：在小鼠、犬类和人类细胞中，CRISPR/Cas9技术成功修正了引起杜氏肌营养不良症的dystrophin基因突变。
  2. 长期效应：由于肌肉组织的长寿命，理论上CRISPR技术能够提供一次性治疗，通过修正致病突变实现正常基因表达。
  3. 临床前研究：已有多项临床前研究表明，基因编辑可以有效恢复肌肉功能，并改善相关症状。

主要结论/意义/创新性 ​

本综述强调了基因组编辑技术在治疗肌肉萎缩症方面的潜力，特别是在纠正致病突变后实现正常基因表达的可能性。CRISPR/Cas9技术为单基因遗传病提供了一种新型的治愈策略，具有显著的临床应用前景和创新性。

研究局限性和未来方向 ​

  1. 安全性问题：基因编辑可能引发脱靶效应，影响其他基因的功能。
  2. 技术推广：尽管实验室研究取得成功，但在临床应用中仍需解决技术转化的难题。
  3. 伦理考量：基因编辑涉及的伦理问题需进一步探讨。

未来的研究方向应集中在提高基因编辑的精准性和安全性，探索在不同动物模型中的应用效果，以及对患者个体化治疗方案的开发。

参考文献 ​

  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)

引用本文的文献 ​

  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 更多 篇文献)

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