Journal
HUMAN GENE THERAPY
Volume 31, Issue 3-4, Pages 241-252Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2019.224
Keywords
Duchenne muscular dystrophy; foamy virus; codon-optimized full-length dystrophin; mdx nude mice; intramuscular transplantation
Categories
Funding
- MRC [G0900872]
- Wellcome Trust PhD studentship [093610/Z/10/A]
- Jefferiss Research Trust Fellowship
- Great Ormond Street Hospital Children's Charity
- MDUK
- MRC Centre for Neuromuscular Diseases
- NIHR BRC at Imperial NHS Trust
- NIHR Great Ormond Street Hospital Biomedical Research Centre
- MRC [G0900872] Funding Source: UKRI
- Wellcome Trust [093610/Z/10/A] Funding Source: Wellcome Trust
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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 (FL-dys) 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 FL-dys open-reading frame and transduce myoblasts derived from a DMD patient. Differentiated myotubes derived from these transduced cells produced FL-dys. 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 FL-dys in nearly all the muscle fibers of donor origin. Furthermore, we showed that the restored FL-dys recruited members of the dystrophin-associated protein complex and neuronal nitric oxide synthase within donor-derived muscle fibers, evidence that the restored dystrophin protein is functional. Dystrophin-expressing donor-derived muscle fibers expressed lower levels of utrophin than host muscle fibers, providing additional evidence of functional improvement of donor-derived myofibers. 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 intramuscular transplantation, representing a promising therapeutic strategy for individual small muscles in DMD.
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