CRISPR Successfully Restores Gene Function in Animal Model of Duchenne Muscular Dystrophy Interview with:
Rhonda Bassel-Duby, Ph.D. and

Dr. Chengzu Long, PhD
Department of Molecular Biology
UT Southwestern Medical Center
Dallas, TX 75390-9148

Medical Research: What is the background for this study? What are the main findings?

Response: Duchenne muscular dystrophy (DMD), which was first described by Duchenne de Boulogne (1806-1875) in 1860s, is one of the most severe and common type of muscular dystrophy. DMD is caused by mutations in the gene for dystrophin (DMD) on the X chromosome and affects approximately 1 in 3500 to 5000 boys. Without dystrophin, a large cytoskeletal protein, muscles degenerate, causing myopathy. Symptoms can be visible between 1 to 6 years old. Most Duchenne muscular dystrophy patients are confined to a wheelchair by age 12. Death of DMD patients usually occurs by age 25, typically from breathing complications and cardiomyopathy. Hence, therapy for Duchenne muscular dystrophy necessitates sustained rescue of skeletal, respiratory and cardiac muscle structure and function. Although several gene therapies have been tested, there is no curative treatment so far.

Duchenne muscular dystrophy arises from a monogenic mutations in dystrophin gene. This makes DMD an ideal disease model for CRISPR-mediated gene editing therapeutics, a major breakthrough in gene engineering in the past three years. This system can remove the defect within the gene.

In 2014, in a first proof of concept study, Olson’s team used CRISPR-mediated gene editing to correct the dystrophin gene mutation in the germline of DMD mouse model. In this new paper, we advanced the same technology to postnatal muscle tissues by delivery gene editing components via a harmless adeno-associated virus. Skeletal and cardiac muscle showed progressive rescue of dystrophin protein.

Medical Research: What should clinicians and patients take away from your report?

Response: Although gene editing holds promise for the foreseeable future, the increase in body size between rodents and patients need to be considered before clinical application. More efficient and high fidelity genome editing and delivery methods in adult tissues is also required for the advancement of the CRISPR/Cas9 system into clinical use.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: For future research, safety issues of the CRISPR system, especially for a high dosage and long-term application, need to be carefully scaled up and evaluated in large animal models of Duchenne muscular dystrophy in preclinical studies. Potential risks such as immunity response, unexpected non-target tissue editing also needs to be evaluated. In addition to heart and skeletal muscle, DMD also affects brain function of patients. Correcting the mutations in the brain also warrants consideration.


Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy

Chengzu Long, Leonela Amoasii, Alex A. Mireault, John R. McAnally, Hui Li, Efrain Sanchez-Ortiz,Samadrita Bhattacharyya, John M. Shelton,Rhonda Bassel-Duby, and Eric N. Olson

Science aad5725Published online 31 December 2015

Rhonda Bassel-Duby, Ph.D. and, & Dr. Chengzu Long, Graduate Student (2016). CRISPR Successfully Restores Gene Function in Animal Model of Duchenne Muscular Dystrophy