Résumé :
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Background A cat model exhibiting a recessive form of lower motor neuron degeneration characterized by a juvenile onset amyotrophy represents a new animal model of spinal muscular atrophy (SMA) and provides opportunities to evaluate therapeutic strategies of motor neuron diseases. The aim of our study is to test new approaches for therapeutic gene transfer in the motor neurons. The vascular endothelial growth factor (VEGF), which is known as a neuroprotective agent, was initially chosen as the therapeutic factor. Method An AAV1 vector encoding VEGF was injected into the motor cortex or the cisterna magna of 7 weeks-old kittens. Detection of the vector genome and expression was achieved using PCR and RT-PCR, respectively, in the brain, spinal cord, nerves and muscles. The therapeutic efficiency of the VEGF gene transfer was evaluated by neurological follow-up and electromyographic exams. Results After injection of the AAV1-VEGF vector into the cortex, both the DNA and the mRNA corresponding to the transgene were detected throughout the spinal cord, suggesting an anterograde transport of the vector via the cortico-spinal pathway up to the motor neurons. However, there was no therapeutic effect of the VEGF gene transfer in the affected kittens, due to an insufficient production of the therapeutic protein in the spinal cord. In order to improve spinal cord transduction, intrathecal injections of AAV1 and AAV9-VEGF were performed in kittens, which led to a strong expression of the therapeutic gene in the spinal cord. Conclusion Intracortical injection of a recombinant AAV in a feline model of SMA can lead to the diffusion of the vector throughout the spinal cord via the cortico-spinal pathway. On the other hand, the intrathecal rAAV injection in the kitten is particularly efficient for gene transfer to the spinal cord. These preliminary results could open interesting perspectives for the therapy of motor neuron degenerative diseases. To contact the author:: beatrice.joussemet@univ-nantes.fr.
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