Gene transfer strategy to promote axonal regeneration in the injured spinal cord : towards clinical application

Session : Viral Vectors

International audience

English. In spinal cord injury (SCI), reactive astrocytes build-up a dense cellular structure, the glial scar, that forms both physical and chemical barriers considered to be detrimental for axonal regeneration. Reactive astrocytes present hypertrophic processes resulting mainly from increased expression of glial fibrillary acidic protein (GFAP) and vimentin, two astrocyte cytoskeletal intermediate filament proteins. It had been shown, in mice knockout for both GFAP and vimentin, that due to the absence of glial reactivity, reinnervation and partial motor recovery occurred after lateral spinal cord hemisection. In order to translate this proof of principle into a therapeutic strategy, we have developed an experimental approach based on the use of siRNA carried by lentiviral vectors. We have developed lentiviral vectors Lv-siGFAP and Lv-siVIM which inhibit the in vitro formation of a glial scar in a Scratch model of lesion. Here we report that in a mouse model of SCI, intraspinal application of Ientiviral vectors Lv-shGFAP and Lv-shVIM efficiently reduces glial reactivity by silencing GFAP alone or associated with vimentin, permits axonal regrowth and improves functional motor recovery. With the objective of translation to clinics, we are adapting the work performed on mice to a large animal model (domestic swine), in order to mimic the clinical settings. We thus first designed and generated lentiviral vectors Lv-siGFAPsw able to inhibit GFAP expression in swine astrocytes. In parallel, we started to define the experimental surgical procedures of lentiviral transduction in the swine injured spinal cord by hemisection.