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Autologous Cell Therapy Approach for Duchenne Muscular Dystrophy using PiggyBac Transposons and Mesoangioblasts
- 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
- Subjects :
- Male
0301 basic medicine
mdx mouse
morpholinos
Duchenne muscular dystrophy
Cell- and Tissue-Based Therapy
Gene Dosage
Fluorescent Antibody Technique
Gene Expression
Mice, SCID
Myoblasts
Cell therapy
Mice
Genes, Reporter
genetic correction
Gene Order
Drug Discovery
mesoangioblasts
Transgenes
Transposon integration
Gene Transfer Techniques
muscle stem-cells
Phenotype
Molecular Medicine
Original Article
muscle fatigue
delivery
Dystrophin
musculoskeletal diseases
transposon vectors
muscular dystrophies
cell therapy
dystrophin
mouse model
Genetic Vectors
Biology
Transplantation, Autologous
Cell Line
03 medical and health sciences
expression
Genetics
medicine
Animals
Progenitor cell
Molecular Biology
Pharmacology
Mesoangioblast
medicine.disease
Molecular biology
Muscular Dystrophy, Duchenne
Transplantation
Disease Models, Animal
030104 developmental biology
DNA Transposable Elements
Mice, Inbred mdx
biology.protein
Subjects
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