Amyotrophic lateral sclerosis (ALS) is mainly a sporadic neurodegenerative disorder characterized by loss of cortical and spinal motoneurons. Some familial ALS cases (FALS) have been linked to dominant mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Transgenic mice overexpressing a mutated form of human SOD1 with a Gly93Ala substitution develop progressive muscle wasting and paralysis as a result of spinal motoneuron loss and die at 5 to 6 months. We investigated the effects of neurotrophic factor gene delivery in this FALS model. Intramuscular injection of an adenoviral vector encoding cardiotrophin-1 (CT-1) in SOD1G93A newborn mice resulted in systemic delivery of CT-1, supplying motoneurons with a continuous source of trophic factor. CT-1 delayed the onset of motor impairment as assessed in the rotarod test. Axonal degeneration was slowed and skeletal muscle atrophy was largely reduced by CT-1 treatment. By monitoring the amplitude of the evoked motor response, we showed that the time-course of motor impairment was significantly decreased by CT-1 treatment. Thus, adenovirus-mediated gene transfer of neurotrophic factors might delay neurogenic muscular atrophy and progressive neuromuscular deficiency in ALS patients.

No 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.

No abstract

No abstract

No abstract

No abstract

No abstract