Autologous Cell Therapy Approach for Duchenne Muscular Dystrophy using PiggyBac Transposons and Mesoangioblasts.
Details
Serval ID
serval:BIB_0BE77D405BD4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Autologous Cell Therapy Approach for Duchenne Muscular Dystrophy using PiggyBac Transposons and Mesoangioblasts.
Journal
Molecular therapy
ISSN
1525-0024 (Electronic)
ISSN-L
1525-0016
Publication state
Published
Issued date
04/04/2018
Peer-reviewed
Oui
Volume
26
Number
4
Pages
1093-1108
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease currently without cure. We investigated the use of the PiggyBac transposon for full-length dystrophin expression in murine mesoangioblast (MABs) progenitor cells. DMD murine MABs were transfected with transposable expression vectors for full-length dystrophin and transplanted intramuscularly or intra-arterially into mdx/SCID mice. Intra-arterial delivery indicated that the MABs could migrate to regenerating muscles to mediate dystrophin expression. Intramuscular transplantation yielded dystrophin expression in 11%-44% of myofibers in murine muscles, which remained stable for the assessed period of 5 months. The satellite cells isolated from transplanted muscles comprised a fraction of MAB-derived cells, indicating that the transfected MABs may colonize the satellite stem cell niche. Transposon integration site mapping by whole-genome sequencing indicated that 70% of the integrations were intergenic, while none was observed in an exon. Muscle resistance assessment by atomic force microscopy indicated that 80% of fibers showed elasticity properties restored to those of wild-type muscles. As measured in vivo, transplanted muscles became more resistant to fatigue. This study thus provides a proof-of-principle that PiggyBac transposon vectors may mediate full-length dystrophin expression as well as functional amelioration of the dystrophic muscles within a potential autologous cell-based therapeutic approach of DMD.
Keywords
Animals, Cell Line, Cell- and Tissue-Based Therapy/methods, DNA Transposable Elements, Disease Models, Animal, Dystrophin/genetics, Fluorescent Antibody Technique, Gene Dosage, Gene Expression, Gene Order, Gene Transfer Techniques, Genes, Reporter, Genetic Vectors/genetics, Male, Mice, Mice, Inbred mdx, Mice, SCID, Muscular Dystrophy, Duchenne/genetics, Muscular Dystrophy, Duchenne/pathology, Muscular Dystrophy, Duchenne/physiopathology, Muscular Dystrophy, Duchenne/therapy, Myoblasts/metabolism, Myoblasts/transplantation, Phenotype, Transgenes, Transplantation, Autologous, Duchenne muscular dystrophy, cell therapy, dystrophin, mesoangioblasts, muscle fatigue, muscular dystrophies, transposon vectors
Pubmed
Web of science
Open Access
Yes
Create date
19/11/2019 15:34
Last modification date
20/11/2019 6:26