Full-length dysferlin expression driven by engineered human dystrophic blood-derived CD133+ stem cells
Articolo
Data di Pubblicazione:
2013
Citazione:
Full-length dysferlin expression driven by engineered human dystrophic blood-derived CD133+ stem cells / M. Meregalli, C. Navarro, C. Sitzia, A. Farini, E. Montani, N. Wein, P. Razini, C. Beley, L. Cassinelli, D. Parolini, M. Belicchi, D. Parazzoli, L. Garcia, Y. Torrente. - In: THE FEBS JOURNAL. - ISSN 1742-464X. - 280:23(2013 Sep 04), pp. 6045-6060. [10.1111/febs.12523]
Abstract:
The protein dysferlin is abundantly expressed in skeletal and cardiac
muscles, where its main function is membrane repair. Mutations in the
dysferlin gene are involved in two autosomal recessive muscular
dystrophies: Miyoshi myopathy and limb-girdle muscular dystrophy type
2B. Development of effective therapies remains a great challenge. Strategies
to repair the dysferlin gene by skipping mutated exons, using antisense
oligonucleotides (AONs), may be suitable only for a subset of mutations,
while cell and gene therapy can be extended to all mutations. AON-treated
blood-derived CD133+ stem cells isolated from patients with Miyoshi
myopathy led to partial dysferlin reconstitution in vitro but failed to
express dysferlin after intramuscular transplantation into scid/blAJ dysferlin
null mice. We thus extended these experiments producing the full-length
dysferlin mediated by a lentiviral vector in blood-derived CD133+ stem
cells isolated from the same patients. Transplantation of engineered bloodderived
CD133+ stem cells into scid/blAJ mice resulted in sufficient
dysferlin expression to correct functional deficits in skeletal muscle
membrane repair. Our data suggest for the first time that lentivirus-mediated
delivery of full-length dysferlin in stem cells isolated from Miyoshi
myopathy patients could represent an alternative therapeutic approach for
treatment of dysferlinopathies.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
dysferlin; exon skipping; gene therapy; muscular dystrophy
Elenco autori:
M. Meregalli, C. Navarro, C. Sitzia, A. Farini, E. Montani, N. Wein, P. Razini, C. Beley, L. Cassinelli, D. Parolini, M. Belicchi, D. Parazzoli, L. Garcia, Y. Torrente
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