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Stem Cell-Mediated Exon Skipping of the Dystrophin Gene by the Bystander Effect

[ Vol. 15 , Issue. 6 ]

Author(s):

Mirella Meregalli, Andrea Farini, Clementina Sitzia, Cyriaque Beley, Paola Razini, Letizia Cassinelli, Federica Colleoni, Paola Frattini, Nadia Santo, Elisabetta Galbiati, Davide Prosperi, Alessandro Tavelli, Marzia Belicchi, Luis Garcia and Yvan Torrente   Pages 563 - 571 ( 9 )

Abstract:


Duchenne muscular dystrophy (DMD) is characterized by the loss of a functional dystrophin protein; the muscles of DMD patients progressively degenerate as a result of mechanical stress during contractions, and the condition eventually leads to premature death. By means antisense oligonucleotides (AONs), it is possible to modulate pre-mRNA splicing eliminating mutated exons and restoring dystrophin open reading frame. To overcome the hurdles in using AONs for therapeutic interventions, we exerted engineered human DMD stem cells with a lentivirus, which permanently and efficiently delivered the cloned AONs. Here we describe for the first time the exosome-mediated release of AONs from engineered human DMD CD133+ stem cells allowing the rescue of murine dystrophin expression. Finally, upon release, AONs could be internalized by host cells suggesting a potential role of exosomes acting as vesicular carriers for DMD gene therapy.

Keywords:

Bystander effect, Myogenic stem cells, Delivery of exon skipping machinery.

Affiliation:

Laboratorio Cellule Staminali- Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti - Universita degli Studi di Milano Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.



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