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Autologous Cell Therapy Approach for Duchenne Muscular Dystrophy using PiggyBac Transposons and Mesoangioblasts

Authors :
Marisa Jaconi
Graziella Messina
Flavio Lorenzo Ronzoni
Małgorzata Lekka
Olivier M. Dorchies
Nicolas Mermod
Lionel O. Mavoungou
Stefania Antonini
L. Neff
Emanuel Schmid-Siegert
Joanna Zemła
Pavithra S. Iyer
Source :
Molecular Therapy, 26 (4)
Publication Year :
2018
Publisher :
ETH Zurich, 2018.

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.<br />Molecular Therapy, 26 (4)<br />ISSN:1525-0016<br />ISSN:1525-0024

Details

Language :
English
ISSN :
15250016 and 15250024
Database :
OpenAIRE
Journal :
Molecular Therapy, 26 (4)
Accession number :
edsair.doi.dedup.....463125bc692cb32fe26c14b6b4ac548d
Full Text :
https://doi.org/10.3929/ethz-b-000255705