In vivo gene editing in dystrophic mouse muscle and muscle stem cells#

Details

• Alternative Title:
  Science
• Personal Author:
  Tabebordbar, Mohammadsharif ; Zhu, Kexian ; Cheng, Jason K.W. ; Chew, Wei Leong ; Widrick, Jeffrey J. ; Yan, Winston X. ; Maesner, Claire ; Wu, Elizabeth Y. ; Xiao, Ru ; Ran, F. Ann ; Cong, Le ; Zhang, Feng ; Vandenberghe, Luk H. ; Church, George M. ; Wagers, Amy J.
• Description:
  Frame-disrupting mutations in the DMD gene, encoding dystrophin, compromise myofiber integrity and drive muscle deterioration in Duchenne muscular dystrophy (DMD). Removing one or more exons from the mutated transcript can produce an in-frame mRNA and a truncated, but still functional, protein. In this study, we developed and tested a direct gene-editing approach to induce exon deletion and recover dystrophin expression in the mdx mouse model of DMD. Delivery by adeno-associated virus (AAV) of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 endonucleases coupled with paired guide RNAs flanking the mutated Dmd exon23 resulted in excision of intervening DNA and restored the Dmd reading frame in myofibers, cardiomyocytes, and muscle stem cells after local or systemic delivery. AAV-Dmd CRISPR treatment partially recovered muscle functional deficiencies and generated a pool of endogenously corrected myogenic precursors in mdx mouse muscle.
• Subjects:
  Animals Article Clustered Regularly Interspaced Short Palindromic Repeats CRISPR-Cas Systems Dependovirus Disease Models, Animal Exons Frameshift Mutation Genetic Therapy Mice Mice, Inbred Mdx Muscle, Skeletal Muscular Dystrophy, Duchenne Myocardium RNA, Messenger Satellite Cells, Skeletal Muscle Sequence Deletion Transduction, Genetic

  More +
• Source:
  Science. 351(6271):407-411.
• Pubmed ID:
  26721686
• Pubmed Central ID:
  PMC4924477
• Document Type:
  Journal Article
• Funding:
  1DP2OD004345/OD/NIH HHS/United States ; 5DP1-MH100706/DP/NCCDPHP CDC HHS/United States ; 5PN2EY018244/EY/NEI NIH HHS/United States ; 5R01DK097768-03/DK/NIDDK NIH HHS/United States ; 5U01HL100402/HL/NHLBI NIH HHS/United States ; DP1 MH100706/MH/NIMH NIH HHS/United States ; DP2 OD004345/OD/NIH HHS/United States ; P50 HG005550/HG/NHGRI NIH HHS/United States ; P50 HG005550/HG/NHGRI NIH HHS/United States ; PN2 EY018244/EY/NEI NIH HHS/United States ; R01 DK097768/DK/NIDDK NIH HHS/United States ; R01 MH110049/MH/NIMH NIH HHS/United States ; T2GM007753/GM/NIGMS NIH HHS/United States ; U01 HL100402/HL/NHLBI NIH HHS/United States ; Howard Hughes Medical Institute/United States
• Volume:
  351
• Issue:
  6271
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:6eb5ee2f2b49ca92e266d1285fa7253be862809e414263f94c21d48055917c59
• Download URL:
  https://stacks.cdc.gov/view/cdc/40098/cdc_40098_DS1.pdf
• File Type:
  [PDF - 634.42 KB ]