In vivo electrotransfer of the cardiotrophin-1 gene into skeletal muscle slows down progression of motor neuron degeneration in pmn mice

Abstract

Among all vectors designed for gene therapy purposes, adenovirus appears to be the most efficient in vivo vehicle to transduce the broadest spectrum of cellular targets. However, the deleterious immunogenicity of this viral vector impedes its use in chronic diseases. Non-viral vectors, such as naked DNA, are attractive alternatives for safety and technical issues, such as scale-up production. Naked DNA injection, greatly improved when combined with electroporation, showed great potential in adult animals, especially when directed to the muscle. We have recently proven the therapeutic effect of a neonatal single intramuscular injection of a cardiotrophin-1 (CT-1)-encoding adenovirus in a hereditary disease mouse model of human motor neuron disease, the progressive motor neuronopathy (pmn) mutant. We now demonstrate that a single injection/electroporation of a CT-1-encoding plasmid in neonate pmn mice is almost as efficient as adenovirus-mediated gene transfer with respect to survival, muscular function and neuroprotection of the animals. Treated mice gain global weight, their mean lifespan is extended by 25%, all their electromyographic parameters are improved and myelinated axons of their phrenic nerves are protected. Moreover, we show that re-injection/electroporation leads to improvements in this neuroprotection. We therefore demonstrate for the first time the therapeutic efficacy of neonatal intramuscular DNA injection/electroporation in a murine model of a human hereditary disorder.

FVIII gene delivery by muscle electroporation corrects murine hemophilia A

“…Sustained insulin expression from electroporated skeletal muscle for up to 6 weeks significantly improved fasting hyperglycemia and prevented body weight loss of diabetic nude mice [32]. Electrically mediated naked plasmid gene transfer has been shown to reduce the severity of viral myocarditis [33] and genetically determined motor neuron degeneration [34].…”

Plasmid DNA electrotransfer for intracellular and secreted proteins expression: new methodological developments and applications

“…Plasma insulin concentration reached by two injections of 100 µg of plasmid led to significant reduced hyperglycemia in diabetic mice [26]. In another study, a single electrotransfer of a cardiotrophin-1 encoding plasmid in neonate progressive motor neuropathy resulted in improvement of all electromyographic parameters, protection of myelinated axons and phrenic nerves, and an increase in the mean lifetime of 25% [76].…”

DNA electrotransfer: its principles and an updated review of its therapeutic applications

“…36,37 These conditions have been adapted to other tissues: in tumours, transfection levels that depended on the tumour type were found maximal using eight identical pulses of 20 ms and 500 or 600 V/ cm at a repetition frequency of 1 or 2 Hz, 38 250 V/cm in the liver, 39 and 500 or 750 V/cm for the skeletal muscle in neonate mice (7-10 days old mice). 40 …”