Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy

David G. Ousterout, Ami M. Kabadi, Pratiksha I. Thakore, William H. Majoros, Timothy E. Reddy and Charles A. Gersbach ()
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David G. Ousterout: Duke University, Room 136 Hudson Hall, Box 90281
Ami M. Kabadi: Duke University, Room 136 Hudson Hall, Box 90281
Pratiksha I. Thakore: Duke University, Room 136 Hudson Hall, Box 90281
William H. Majoros: Program in Computational Biology and Bioinformatics, Duke University
Timothy E. Reddy: Center for Genomic and Computational Biology, Duke University
Charles A. Gersbach: Duke University, Room 136 Hudson Hall, Box 90281

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract The CRISPR/Cas9 genome-editing platform is a promising technology to correct the genetic basis of hereditary diseases. The versatility, efficiency and multiplexing capabilities of the CRISPR/Cas9 system enable a variety of otherwise challenging gene correction strategies. Here, we use the CRISPR/Cas9 system to restore the expression of the dystrophin gene in cells carrying dystrophin mutations that cause Duchenne muscular dystrophy (DMD). We design single or multiplexed sgRNAs to restore the dystrophin reading frame by targeting the mutational hotspot at exons 45–55 and introducing shifts within exons or deleting one or more exons. Following gene editing in DMD patient myoblasts, dystrophin expression is restored in vitro. Human dystrophin is also detected in vivo after transplantation of genetically corrected patient cells into immunodeficient mice. Importantly, the unique multiplex gene-editing capabilities of the CRISPR/Cas9 system facilitate the generation of a single large deletion that can correct up to 62% of DMD mutations.

Date: 2015
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DOI: 10.1038/ncomms7244

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