Development of a therapeutic approach for Spinal Muscular Atrophy with Respiratory Distress (SMARD1) using human induced pluripotent stem cell-derived neural stem cells and motor neurons

Spinal Muscular Atrophy with Respiratory Distress (SMARD1) is an autosomal recessive form of infantile motor neuron disease that induces diaphragmatic paralysis and severe progressive muscle weakness. The pathogenesis of SMARD1 is incompletely characterized and currently, no effective therapy is available. SMARD1 is caused by mutations in the gene that encodes the immunoglobulin micro-binding protein 2 (IGHMBP2). Recently we have reported the potential of motor neuron transplantation to ameliorate the disease phenotype in the nmd mouse, an animal model of SMARD1. The present project aims to advance this therapeutic strategy towards clinical translation with the use of human neural stem cells (NSC) and motor neurons derived from induced pluripotent stem cells (iPSCs). We will generate iPSCs from healthy human fibroblasts that are free of vector and transgene sequences. These iPSCs will be differentiated into NSCs and motor neurons, and then transplanted into the spinal cord of SMARD1 mice. We will evaluate the therapeutic potential and the mechanisms that favor engraftment. This project will contribute to the development of novel therapeutic strategies for SMARD1 and other genetic motor neuron diseases.