In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy

Christopher E. Nelson; Chady H. Hakim; David G. Ousterout; Pratiksha I. Thakore; Eirik A. Moreb; Ruth M. Castellanos Rivera; Sarina Madhavan; Xiufang Pan; F. Ann Ran; Winston X. Yan; Aravind Asokan; Feng Zhang; Dongsheng Duan; Charles A. Gersbach

doi:10.1126/science.aad5143

ReportGENE EDITING

In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy

Christopher E. Nelson¹,²,
Chady H. Hakim³,
David G. Ousterout¹,²,
Pratiksha I. Thakore¹,²,
Eirik A. Moreb¹,²,
Ruth M. Castellanos Rivera⁴,
Sarina Madhavan¹,²,
Xiufang Pan³,
F. Ann Ran⁵,⁶,
Winston X. Yan⁵,⁷,⁸,
Aravind Asokan⁴,
Feng Zhang⁵,⁹,¹⁰,¹¹,
Dongsheng Duan³,¹²,
Charles A. Gersbach¹,²,¹³,*

¹Department of Biomedical Engineering, Duke University, Durham, NC, USA.
²Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
³Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA.
⁴Gene Therapy Center, Departments of Genetics, Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶Society of Fellows, Harvard University, Cambridge, MA, USA.
⁷Graduate Program in Biophysics, Harvard Medical School, Boston, MA, USA.
⁸Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, USA.
⁹McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹¹Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹²Department of Neurology, University of Missouri, Columbia, MO, USA.
¹³Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, USA.

↵*Corresponding author. E-mail: charles.gersbach{at}duke.edu

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Science 31 Dec 2015:
aad5143
DOI: 10.1126/science.aad5143

Christopher E. Nelson

Department of Biomedical Engineering, Duke University, Durham, NC, USA.Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.

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Chady H. Hakim

Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA.

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David G. Ousterout

Department of Biomedical Engineering, Duke University, Durham, NC, USA.Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.

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Pratiksha I. Thakore

Department of Biomedical Engineering, Duke University, Durham, NC, USA.Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.

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Eirik A. Moreb

Department of Biomedical Engineering, Duke University, Durham, NC, USA.Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.

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Ruth M. Castellanos Rivera

Gene Therapy Center, Departments of Genetics, Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

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Sarina Madhavan

Department of Biomedical Engineering, Duke University, Durham, NC, USA.Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.

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Xiufang Pan

Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA.

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F. Ann Ran

Broad Institute of MIT and Harvard, Cambridge, MA, USA.Society of Fellows, Harvard University, Cambridge, MA, USA.

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Winston X. Yan

Broad Institute of MIT and Harvard, Cambridge, MA, USA.Graduate Program in Biophysics, Harvard Medical School, Boston, MA, USA.Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, USA.

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Aravind Asokan

Gene Therapy Center, Departments of Genetics, Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

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Feng Zhang

Broad Institute of MIT and Harvard, Cambridge, MA, USA.McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

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Dongsheng Duan

Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA.Department of Neurology, University of Missouri, Columbia, MO, USA.

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Charles A. Gersbach

Department of Biomedical Engineering, Duke University, Durham, NC, USA.Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, USA.

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For correspondence: charles.gersbach@duke.edu

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Abstract

Duchenne muscular dystrophy (DMD) is a devastating disease affecting about 1 out of 5000 male births and caused by mutations in the dystrophin gene. Genome editing has the potential to restore expression of a modified dystrophin gene from the native locus to modulate disease progression. In this study, adeno-associated virus was used to deliver the CRISPR/Cas9 system to the mdx mouse model of DMD to remove the mutated exon 23 from the dystrophin gene. This includes local and systemic delivery to adult mice and systemic delivery to neonatal mice. Exon 23 deletion by CRISPR/Cas9 resulted in expression of the modified dystrophin gene, partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle, improvement of muscle biochemistry, and significant enhancement of muscle force. This work establishes CRISPR/Cas9-based genome editing as a potential therapy to treat DMD.

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In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy

Abstract

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