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Scientific Articles

Enhanced CRISPR-Cas9 Correction of Duchenne Muscular Dystrophy in Mice by a Self-Complementary AAV Delivery System

key information

source: Science Advances

year: 2020

authors: Yu Zhang, Hui Li, Yi-Li Min, Efrain Sanchez-Ortiz, Jian Huang, Alex A. Mireault, John M. Shelton, Jiwoong Kim, Pradeep P. A. Mammen, Rhonda Bassel-Duby, Eric N. Olson


Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disease caused by mutations in the dystrophin gene (DMD). Previously, we applied CRISPR-Cas9–mediated “single-cut” genome editing to correct diverse genetic mutations in animal models of DMD. However, high doses of adeno-associated virus (AAV) are required for efficient in vivo genome editing, posing challenges for clinical application.

 In this study, we packaged Cas9 nuclease in single-stranded AAV (ssAAV) and CRISPR single guide RNAs in self-complementary AAV (scAAV) and delivered this dual AAV system into a mouse model of DMD. The dose of scAAV required for efficient genome editing were at least 20-fold lower than with ssAAV. Mice receiving systemic treatment showed restoration of dystrophin expression and improved muscle contractility. 

These findings show that the efficiency of CRISPR-Cas9–mediated genome editing can be substantially improved by using the scAAV system. This represents an important advancement toward therapeutic translation of genome editing for DMD.

organization: University of Texas Southwestern Medical Center, USA

DOI: 10.1126/sciadv.aay6812

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