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CRISPR/Cas9 Technology in Restoring Dystrophin Expression in iPSC-Derived Muscle Progenitors
Published on: September 14, 2019
CRISPR Therapeutics for Duchenne Muscular Dystrophy
Esra Erkut1, Toshifumi Yokota1,2
1Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, 8613-114 Street, Edmonton, AB T6G 2H7, Canada.
Abstract:
Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder with a prevalence of approximately 1 in 3500-5000 males. DMD manifests as childhood-onset muscle degeneration, followed by loss of ambulation, cardiomyopathy, and death in early adulthood due to a lack of functional dystrophin protein. Out-of-frame mutations in the dystrophin gene are the most common underlying cause of DMD. Gene editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system is a promising therapeutic for DMD, as it can permanently correct DMD mutations and thus restore the reading frame, allowing for the production of functional dystrophin. The specific mechanism of gene editing can vary based on a variety of factors such as the number of cuts generated by CRISPR, the presence of an exogenous DNA template, or the current cell cycle stage. CRISPR-mediated gene editing for DMD has been tested both in vitro and in vivo, with many of these studies discussed herein. Additionally, novel modifications to the CRISPR system such as base or prime editors allow for more precise gene editing. Despite recent advances, limitations remain including delivery efficiency, off-target mutagenesis, and long-term maintenance of dystrophin. Further studies focusing on safety and accuracy of the CRISPR system are necessary prior to clinical translation.
Insights
Gene editing using CRISPR technology offers a promising approach to correct mutations causing Duchenne muscular dystrophy (DMD). This method aims to restore functional dystrophin protein, though challenges in delivery and safety require further research before clinical application.
Area of Science:
- Biotechnology
- Genetics
- Neuromuscular Disorders
Background:
- Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by mutations in the dystrophin gene, leading to progressive muscle degeneration.
- The absence of functional dystrophin protein results in muscle weakness, loss of ambulation, cardiomyopathy, and premature death.
Purpose of the Study:
- To review the application of clustered regularly interspaced short palindromic repeats (CRISPR) gene editing technology as a potential therapeutic strategy for Duchenne muscular dystrophy.
- To discuss the mechanisms, advancements, and challenges associated with CRISPR-based gene editing for DMD.
Main Methods:
- Review of in vitro and in vivo studies investigating CRISPR-mediated gene editing for DMD.
- Discussion of various CRISPR system modifications, including base and prime editing, for enhanced precision.
- Analysis of factors influencing gene editing efficiency, such as cell cycle stage and DNA template presence.
Main Results:
- CRISPR gene editing demonstrates potential to correct DMD-causing mutations by restoring the dystrophin gene reading frame.
- Studies have shown successful application of CRISPR in both laboratory and animal models of DMD.
- Novel CRISPR variants like base and prime editors offer improved precision for gene correction.
Conclusions:
- CRISPR gene editing is a promising therapeutic avenue for Duchenne muscular dystrophy, with the potential for permanent mutation correction.
- Key challenges including delivery efficiency, off-target effects, and long-term protein expression must be addressed.
- Further research on the safety and accuracy of CRISPR systems is crucial for successful clinical translation.
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