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Restoration of Functional Full-Length Dystrophin After Intramuscular Transplantation of Foamy Virus-Transduced Myoblasts

Meng, J; Sweeney, N; Doreste, B; Muntoni, F; McClure, M; Morgan, J; (2020) Restoration of Functional Full-Length Dystrophin After Intramuscular Transplantation of Foamy Virus-Transduced Myoblasts. Human Gene Therapy , 31 (3-4) 10.1089/hum.2019.224. Green open access

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Abstract

Stem cell therapy is a promising strategy to treat muscle diseases such as Duchenne muscular dystrophy (DMD). To avoid immune-rejection of donor cells or donor-derived muscle, autologous cells which have been genetically modified to express dystrophin are preferable to cells derived from healthy donors. Restoration of full-length dystrophin using viral vectors is extremely challenging, due to the limited packaging capacity of the vectors, but we have recently shown that either a foamy viral or lentiviral vector is able to package full-length dystrophin open- reading-frame and transduce myoblasts derived from a DMD patient. Differentiated myotubes derived from these transduced cells produced full-length dystrophin. Here, we transplanted the foamy viral-dystrophin corrected DMD myoblasts intramuscularly into mdx nude mice, and showed that the transduced cells contributed to muscle regeneration, expressing full-length dystrophin in nearly all the muscle fibres of donor origin. Further, we showed that the restored full-length dystrophin recruited members of the dystrophin- associated protein complex and nNOS within donor-derived muscle fibres, evidence that the restored dystrophin protein is functional. Dystrophin-expressing donor-derived muscle fibres expressed lower levels of utrophin than host muscle fibres, providing additional evidence of functional improvement of donor-derived myofibres. This is the first in vivo evidence that foamy virus vector transduced DMD myoblasts can contribute to muscle regeneration and mediate functional dystrophin restoration following their intra-muscular transplantation, representing a promising therapeutic strategy for individual small muscles in DMD.

Type: Article
Title: Restoration of Functional Full-Length Dystrophin After Intramuscular Transplantation of Foamy Virus-Transduced Myoblasts
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1089/hum.2019.224
Publisher version: https://doi.org/10.1089/hum.2019.224
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Duchenne muscular dystrophy, foamy virus, codon-optimized full-length dystrophin, mdx nude mice, intramuscular transplantation
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10087834
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