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.
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Meng_Restoration of functional full-length dystrophin after intramuscular transplantation of Foamy Virus-transduced myoblasts_AAM.pdf - Accepted Version Download (1MB) | Preview |
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.
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