New publication in Molecular Therapy !

Short-lived recombinant adeno-associated virus transgene expression in dystrophic muscle is associated with oxidative damage to transgene mRNA.

Jean-Baptiste Dupont1–3, Benoit Tournaire1–3, Christophe Georger4, Béatrice Marolleau4, Laurence Jeanson-Leh4, Mireille Ledevin5, Pierre Lindenbaum2,3,6, Emilie Lecomte1–3, Benjamin Cogné1–3, Laurence Dubreil5, Thibaut Larcher5, Bernard Gjata4, Laetitia Van Wittenberghe4, Caroline Le Guiner1–4, Magalie Penaud-Budloo1–3, Richard O Snyder1,7,8, Philippe Moullier1–3,7 and Adrien Léger1

Preclinical gene therapy strategies using recombinant adeno-associated virus (AAV) vectors in animal models of Duchenne muscular dystrophy have shown dramatic phenotype improvements, but long-lasting efficacy remains questionable. It is believed that in dystrophic muscles, transgene persistence is hampered, notably by the progressive loss of therapeutic vector genomes resulting from muscle fibers degeneration. Intracellular metabolic perturbations resulting from dystrophin deficiency could also be additional factors impacting on rAAV genomes and transgene mRNA molecular fate. In this study, we showed that rAAV genome loss is not the only cause of reduced transgene mRNA level and we assessed the contribution of transcriptional and post-transcriptional factors. We ruled out the implication of transgene silencing by epigenetic mechanisms and demonstrated that rAAV inhibition occurred mostly at the post-transcriptional level. Since Duchenne muscular dystrophy (DMD) physiopathology involves an elevated oxidative stress, we hypothesized that in dystrophic muscles, transgene mRNA could be damaged by oxidative stress. In the mouse and dog dystrophic models, we found that rAAV-derived mRNA oxidation was increased. Interestingly, when a high expression level of a therapeutic transgene is achieved, oxidation is less pronounced. These findings provide new insights into rAAV transductions in dystrophic muscles, which ultimately may help in the design of more effective clinical trials.
Molecular Therapy — Methods & Clinical Development (2015) 2, 15010; doi:10.1038/mtm.2015.10; published online 8 April 2015

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