DEVELOPMENT OF CELLULAR AND MOLECULAR THERAPEUTIC APPROACHES FOR SPINAL MUSCULAR ATROPHY WITH RESPIRATORY DISTRESS (SMARD1)

SMARD1 is an autosomal recessive form of infantile motor neuron disease inducing diaphragmatic paralysis and severe progressive muscle weakness which pathogenesis is incompletely characterised and no effective therapy is now available. It is caused by mutations involving the gene encoding the immunoglobulin micro-binding protein 2 (IGMBP2). Recently we have demonstrated the potential of a primitive subpopulation of neural stem cells (NSCs) to modify disease progression of nmd mouse, an animal model of SMARD1 after transplantation in the CNS. The present project is aiming at the amelioration of this therapeutic strategy. On this purpose we will focus on the following research lines: 1) To increase the generation of the motor neuronal phenotype through the activation of the specific gene expression program; 2) To maximize migration from cerebrospinal fluid and survival of transplanted NSCs into the spinal cord; 3) To promote MN connections with muscle by blocking myelin’s inhibitor signals or by stimulating axonal extension using neurotrophic factors; 4) To evaluate the role of distal axonal and neuromuscular plate dysfunctions; 5) To identify the molecular interaction between transplanted stem cells and MNs and the mechanisms that lead to neurogenesis in the spinal cord. This project may contribute to the development of therapeutic strategies for SMARD1 and other motor neurons diseases.