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Tytuł pozycji:

Full-length dystrophin restoration via targeted exon integration by AAV-CRISPR in a humanized mouse model of Duchenne muscular dystrophy.

Tytuł :
Full-length dystrophin restoration via targeted exon integration by AAV-CRISPR in a humanized mouse model of Duchenne muscular dystrophy.
Autorzy :
Pickar-Oliver A; Department of Biomedical Engineering, Room 1427 FCIEMAS, 101 Science Drive, Box 90281, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.
Gough V; Department of Biomedical Engineering, Room 1427 FCIEMAS, 101 Science Drive, Box 90281, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.
Bohning JD; Department of Biomedical Engineering, Room 1427 FCIEMAS, 101 Science Drive, Box 90281, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.
Liu S; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA; Graduate Program in Computational Biology and Bioinformatics, Duke University, Durham, NC 27708, USA.
Robinson-Hamm JN; Department of Biomedical Engineering, Room 1427 FCIEMAS, 101 Science Drive, Box 90281, Duke University, Durham, NC 27708, USA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.
Daniels H; Department of Biomedical Engineering, Room 1427 FCIEMAS, 101 Science Drive, Box 90281, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.
Majoros WH; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA; Center for Statistical Genetics and Genomics, Duke University, Durham, NC 27708, USA; Division of Integrative Genomics, Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA.
Devlin G; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
Asokan A; Department of Biomedical Engineering, Room 1427 FCIEMAS, 101 Science Drive, Box 90281, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Regeneration Next Initiative, Duke University, Durham, NC 27710, USA.
Gersbach CA; Department of Biomedical Engineering, Room 1427 FCIEMAS, 101 Science Drive, Box 90281, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA; Graduate Program in Computational Biology and Bioinformatics, Duke University, Durham, NC 27708, USA; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Regeneration Next Initiative, Duke University, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: .
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Źródło :
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2021 Sep 10. Date of Electronic Publication: 2021 Sep 10.
Publication Model :
Ahead of Print
Typ publikacji :
Journal Article
Język :
English
Imprint Name(s) :
Publication: 2017- : Cambridge, MA : Cell Press
Original Publication: San Diego, CA : Academic Press, 2000-
Contributed Indexing :
Keywords: CRISPR; genome editing; muscular dystrophy; targeted integration; viral vectors
Entry Date(s) :
Date Created: 20210912 Latest Revision: 20211001
Update Code :
20211005
DOI :
10.1016/j.ymthe.2021.09.003
PMID :
34509668
Czasopismo naukowe
Targeted gene-editing strategies have emerged as promising therapeutic approaches for the permanent treatment of inherited genetic diseases. However, precise gene correction and insertion approaches using homology-directed repair are still limited by low efficiencies. Consequently, many gene-editing strategies have focused on removal or disruption, rather than repair, of genomic DNA. In contrast, homology-independent targeted integration (HITI) has been reported to effectively insert DNA sequences at targeted genomic loci. This approach could be particularly useful for restoring full-length sequences of genes affected by a spectrum of mutations that are also too large to deliver by conventional adeno-associated virus (AAV) vectors. Here, we utilize an AAV-based, HITI-mediated approach for correction of full-length dystrophin expression in a humanized mouse model of Duchenne muscular dystrophy (DMD). We co-deliver CRISPR-Cas9 and a donor DNA sequence to insert the missing human exon 52 into its corresponding position within the DMD gene and achieve full-length dystrophin correction in skeletal and cardiac muscle. Additionally, as a proof-of-concept strategy to correct genetic mutations characterized by diverse patient mutations, we deliver a superexon donor encoding the last 28 exons of the DMD gene as a therapeutic strategy to restore full-length dystrophin in >20% of the DMD patient population. This work highlights the potential of HITI-mediated gene correction for diverse DMD mutations and advances genome editing toward realizing the promise of full-length gene restoration to treat genetic disease.
(Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

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