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CRISPR-Cas9 Corrects Mutations in Muscular Dystrophy Patients' Cells

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Duchenne Muscular Dystrophy (DMD) is a progressive muscle wasting disease which proves fatal for most sufferers before they leave their teens. A new study published today suggests that a novel application of the revolutionary gene editing technique CRISPR may offer a solution to this currently incurable disease.

The study’s authors, a collaborative team of researchers from Dallas, New York, and Göttingen in central Germany, pioneered a technique called myoediting that removes mutated sections of the dystrophin gene that cause DMD, restoring normal function to cells with DMD mutations.  The authors say that their approach could restore muscle function in up to 60% of DMD patients.

DMD is caused by a failure to produce a protein called dystrophin, which in healthy people helps link the cytoskeleton, an essential structural component of cells, to the extracellular matrix, which is a mesh of molecules which provides support to the muscle cells. Mutations in the dystrophin gene prevent the production of protein. Without dystrophin, a DMD patient’s muscle cells become leaky, and eventually die, causing a degeneration of muscle tissue that spreads throughout the body, becoming fatal when heart muscles degenerate.

 Dr Eric Olson is a Professor in the Department of Molecular Biology at UT Southwestern and co-authored the study. In a video released alongside the research, Olson said: “DMD is a prime example of the type of disorder that can eventually be corrected by gene editing. There are more than 4000 different mutations in the dystrophin gene that cause DMD, and by correcting those mutation using CRISPR/Cas9 gene editing, the cause of the disease can be eliminated.”

CRISPR-Cas9 is a genome editing system that generates a break or nick at a desired site in the genome, allowing the surrounding gene sequence to be edited as desired; often the aim is to silence a gene or make precise modifications, and specialized CRISPR techniques exist that enable modern cell science to do both effectively. CRISPR is an relatively recent technology, having only been widely used in the last 5 years. 

 The challenge for DMD research has long been the complexity involved in correcting a gene with so many mutations. The solution found by Olson and his team lay in the distribution of these mutations, which are often found in ‘hotspots’ where many mutations are collected together. Myoediting, as described in the research, allows hotspots to be ‘skipped-over’ when the DNA is read as part of the protein-producing process. Rather than filling in every pothole on the dystrophin gene’s badly damaged road, Olson and his team have built a bypass that allows the potholes to be avoided altogether.  The repair process was trialed on cells taken from DMD patients that were converted into stem cells and then reprogrammed as heart muscle cells. Depending on the cells’ mutations, the team were either able to reduce the severity of the DMD mutations or restore the protein’s normal function altogether. 

Olson, who holds the Pogue Distinguished Chair in Research on Cardiac Birth Defects and The Robert A. Welch Distinguished Chair in Science at UT Southwestern, is optimistic about the future of myoediting for DMD: “This is one of the very rare cases in which work has progressed faster and more efficiently than we ever would have expected. I have never been more optimistic about anything that I’ve worked on in my career. Our work to date has shown extraordinary efficacy in correcting this mutation.” 

A few significant hurdles remain between this study and a therapeutic treatment for DMD. CRISPR technologies can often inadvertently target sites on other genes than have similar sequences, so-called ‘off-target effects’ which could lead to undesirable side-effects. Future research will aim to identify and prevent any off-target effects of myoediting and hopefully make this incredibly promising technology a clinical reality. 

Reference: C. Long, H. Li, M. Tiburcy, C. Rodriguez-Caycedo, V. Kyrychenko, H. Zhou, Y. Zhang, Y.-L. Min, J. M. Shelton, P. P. A. Mammen, N. Y. Liaw, W.-H. Zimmermann, R. Bassel-Duby, J. W. Schneider, E. N. Olson, Correction of diverse muscular dystrophy mutations in human engineered heart muscle by single-site genome editing. Sci. Adv. 4, eaap9004 (2018).