[About a phase I gene therapy clinical trial with a full-length dystrophin gene-plasmid in Duchenne/Becker muscular dystrophy].
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.
Fardeau
Michel
M
Institut de Myologie et Inserm U582, Bâtiment Babinski, Groupe Hospitalier Pitié-Salpêtriere, 75651 Paris. m.fardeau@myologie.chups.jussieu.fr
Braun
Serge
S
Romero
Norma B
NB
Hogrel
J Y
JY
Rouche
Andrée
A
Ortega
Véronique
V
Mourot
Brigitte
B
Squiban
Patrick
P
Benveniste
Olivier
O
Herson
Serge
S
D001706:Biopsy; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D016189:Dystrophin / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry; D020388:Muscular Dystrophy, Duchenne / Q000628:therapy*; D010957:Plasmids / Q000235:genetics; D012313:RNA / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016189:Dystrophin; D012313:RNA; D004247:DNA