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

Details

• Alternative Title:
  Science
• Personal Author:
  Nelson, Christopher E. ; Hakim, Chady H. ; Ousterout, David G. ; Thakore, Pratiksha I. ; Moreb, Eirik A. ; Rivera, Ruth M. Castellanos ; Madhavan, Sarina ; Pan, Xiufang ; Ran, F. Ann ; Yan, Winston X. ; Asokan, Aravind ; Zhang, Feng ; Duan, Dongsheng ; Gersbach, Charles A.
• Description:
  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 clustered regularly interspaced short palindromic repeats (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.
• Subjects:
  Animals Article Clustered Regularly Interspaced Short Palindromic Repeats CRISPR-Cas Systems Dependovirus Disease Models, Animal Dystrophin Exons Genetic Therapy Male Mice Mice, Inbred Mdx Muscle, Skeletal Muscular Dystrophy, Duchenne Sequence Deletion

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• Source:
  Science. 351(6271):403-407.
• Pubmed ID:
  26721684
• Pubmed Central ID:
  PMC4883596
• Document Type:
  Journal Article
• Funding:
  R01 NS090634/NS/NINDS NIH HHS/United States ; DP2 OD008586/OD/NIH HHS/United States ; R01 MH110049/MH/NIMH NIH HHS/United States ; DP1-MH100706/DP/NCCDPHP CDC HHS/United States ; T32 GM007753/GM/NIGMS NIH HHS/United States ; P01HL112761/HL/NHLBI NIH HHS/United States ; DP2-OD008586/OD/NIH HHS/United States ; DP1 MH100706/MH/NIMH NIH HHS/United States ; R01NS90634/NS/NINDS NIH HHS/United States ; R01 DK097768/DK/NIDDK NIH HHS/United States ; T32 GM008313/GM/NIGMS NIH HHS/United States ; T32GM007753/GM/NIGMS NIH HHS/United States ; P01 HL112761/HL/NHLBI NIH HHS/United States ; R01HL089221/HL/NHLBI NIH HHS/United States ; R01DK097768/DK/NIDDK NIH HHS/United States ; R01 HL089221/HL/NHLBI NIH HHS/United States
• Volume:
  351
• Issue:
  6271
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:d4e6676515b777dae0a7bcebe1f98e35e945db8ebb2bc0a3620de6b52efdd00b
• Download URL:
  https://stacks.cdc.gov/view/cdc/39629/cdc_39629_DS1.pdf
• File Type:
  [PDF - 1.45 MB ]