RarFais

Human traumatic spinal cord injury (SCI) can lead to permanent loss of sensation and voluntary motor functions of patients, whose life-long disability is a major public health issue. Despite clinical advances in rehabilitation and neuromodulation treatment improving their quality of life, patients still suffer from the devastating consequences of SCI, aggravated by diverse complications. Currently there are no effective clinical interventions, neither acutely nor during the chronic period. This is due to the limited ability of adult human Central Nervous System to self-repair after injury. Barriers to regeneration include impaired revascularization and ischemia, presence of axon growth inhibitors, establishment of a glial fibrous scar, and persistent inflammation. This detrimental environment contributes to progressive neurodegeneration extending the lesion from the initial impact, aggravating the neurological deficits. Fundamental research and preclinal strategies for SCI repair (mainly rodent) have brought important insights into neuro-restoration, but translation to clinical practice is still limited. Due to the complexity of SCI physiopathology, any future therapy will need to combine approaches to overcome the multiple hindrances, and synergistically improve functional recovery. Accordingly, we propose here a novel approach to treat SCI by combining two strategies - for which we demonstrated that, when applied alone to treat acute lesion, they promote locomotor function with complementary effects on tissue restoration in a rat paraplegia model: (i) implantation of a medical device (MD) composed of natural degradable hydrogel designed as biomaterial scaffold to induce tissue remodeling, potentiate axon growth, and modulate inflammation, and (ii) treatment with a neuroprotective drug (that has reached clinical trials for other neuropathologies), to limit spreading of traumatic injury-induced secondary progressive degeneration. The RarFais project is at the crossroad of neurobiology, materials science and bio-imaging, in strong interaction with clinical neurosurgeons. The approach combining biomaterial and drug therapy aims to prevent secondary lesions, and to stimulate structural plasticity favoring recovery of sensori-motor function. In addition to standard techniques to evaluate SCI repair through motor and sensory tests and anatomical analysis, cutting-edge functional neuroimaging (fUS) will evaluate vasculature recovery, a key player in tissue restoration. RarFais project is structured in 3 scientific work packages, each coordinated by one or two PIs who, although independent in their investigation, are tightly linked with regard to their results and objectives. An additional WP will ensure all aspects of project management. WP1 aims at optimizing the MD to better control its degradation rate without negatively impacting its interaction with cells, followed by in vitro screening of formulations on macrophages, before selection of a few for SCI treatment in vivo. WP2 is dedicated to establish the best-suited protocol combining the MD with neuroprotection to reach a synergistic effect on functional recovery. WP3 will add rehabilitation to the combined therapies according to a defined protocol. Finally, RarFais project will target both acute and chronic SCI. The final goal is to propose an innovative and optimized regenerative strategy with a realistic potential for translation to clinical practice. In full line with the objectives of Axis 8.7 “Technologies pour la santé”, RarFais is a multidisciplinary project developing an innovative and optimized regenerative strategy with a realistic potential for translation to clinical practice. It combines in-depth biological insights, sophisticated biomaterial engineering, and up-to-date imaging technology to come up with a Class III MD (i.e. surgically-invasive implant for use in direct contact with central nervous system) to restore normal function of the spinal cord.