A propos d'un essai de Phase I de thérapie génique effectué avec un plasmide contenant l'intégralité du gène dystrophine dans la Myopathie de Duchenne/Becker

Abstract

This is the first gene transfer trial in Duchenne/Becker patients. The aim of the study was to provide evidence on transgene expression and safety of the intramuscular administration of a plasmid containing a full-length dystrophin CDNA. Nine Duchenne/Becker patients, distributed in three cohorts of three patients, were injected into their radialis muscles either once with 200 microg (first cohort) or 600 microg (second cohort) or twice, two weeks apart, with 600 microg plasmidic DNA (third cohort). The patients were enrolled sequentially upon evaluation of the data by an independant pilot committee. In the biopsies taken three weeks after the initial injection from the injected site, the plasmid was detected in all patients. An exogenous dystrophin expression was found in 6/9 patients. The level of expression was low, up to 6 % of weak complete sarcolemmal labelling, and up to 26% of partial sarcolemmal staining. Dystrophin in RNAs were detected by nested RT-PCR in five out of the six biopsies with exogenous dystrophin-positive fibers. Interestingly, neither humoral or cellular antidystrophin responses were observed. No local or general adverse effects were seen. This paves the way for future developments in gene therapy in hereditary muscle diseases, and specifically in Duchenne/Becker myopathies.

Muscular dystrophy: the route to a cure: Genetic and cell therapies

“…Transfer of recombinant genes encoding full-length (~11 kb), mini-(~6.3 kb) or micro-(<5 kb) dystrophins into DMD-affected muscle is one of the proposed therapies to induce dystrophin protein expression 5 . A Phase I clinical trial has been completed in which eukaryotic expression plasmids encoding full-length human dystrophin were injected directly into muscles of DMD patients 6 . Dystrophin expression at low levels was shown in all patients without any safety concerns and notably without a detectable immune response to dystrophin.…”