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November 2016

Genome Editing of Monogenic Neuromuscular Diseases: A Systematic Review

Author Affiliations
  • 1Department of Molecular Biology, Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas
JAMA Neurol. 2016;73(11):1349-1355. doi:10.1001/jamaneurol.2016.3388
Key Points

Question  What is the clinical potential of genome-editing technology for treating neuromuscular monogenic disorders?

Findings  This review describes recent advances in genome-editing technology, the latest applications of the method, and potential clinical applications by highlighting 4 monogenic neuromuscular disorders as examples. Opportunities and obstacles in the path toward efficient and permanent correction of the genetic cause of these disorders are discussed.

Meaning  Genome editing is a powerful, revolutionary approach to permanently eliminate or correct the genetic cause of monogenic diseases and has broad translational potential when efficacy, delivery, and safety issues are addressed.


Importance  Muscle weakness, the most common symptom of neuromuscular disease, may result from muscle dysfunction or may be caused indirectly by neuronal and neuromuscular junction abnormalities. To date, more than 780 monogenic neuromuscular diseases, linked to 417 different genes, have been identified in humans. Genome-editing methods, especially the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 (CRISPR-associated protein 9) system, hold clinical potential for curing many monogenic disorders, including neuromuscular diseases such as Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1.

Objectives  To provide an overview of genome-editing approaches; to summarize published reports on the feasibility, efficacy, and safety of current genome-editing methods as they relate to the potential correction of monogenic neuromuscular diseases; and to highlight scientific and clinical opportunities and obstacles toward permanent correction of disease-causing mutations responsible for monogenic neuromuscular diseases by genome editing.

Evidence Review  PubMed and Google Scholar were searched for articles published from June 30, 1989, through June 9, 2016, using the following keywords: genome editing, CRISPR-Cas9, neuromuscular disease, Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1. The following sources were reviewed: 341 articles describing different approaches to edit mammalian genomes; 330 articles describing CRISPR-Cas9–mediated genome editing in cell culture lines (in vitro) and animal models (in vivo); 16 websites used to generate single-guide RNA; 4 websites for off-target effects; and 382 articles describing viral and nonviral delivery systems. Articles describing neuromuscular diseases, including Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1, were also reviewed.

Findings  Multiple proof-of-concept studies reveal the feasibility and efficacy of genome-editing–meditated correction of monogenic neuromuscular diseases in cultured cells and animal models.

Conclusions and Relevance  Genome editing is a rapidly evolving technology with enormous translational potential once efficacy, delivery, and safety issues are addressed. The clinical impact of this technology is that genome editing can permanently correct disease-causing mutations and circumvent the hurdles of traditional gene- and cell-based therapies.

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