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 type 1 (SMARD1) is a fatal form of infantile motor neuron disease. Currently, there is no cure. We recently reported that motor neuron transplantation can ameliorate the disease phenotype in a SMARD1 mouse model. This is the first report to show that functional restoration of motor units is feasible with transplanted motor neurons in an animal model of human SMARD1. In this project, we explore the therapeutic potential of human neural stem cells (NSCs) and motor neurons derived from induced pluripotent stem cells (iPSCs) as a tool for motor unit replacement in SMARD1. One end-point of the project is to determine which cell type is most effective for cell therapy. We have generated iPSCs from healthy human fibroblasts, without any vector and transgene sequences. These cells can be differentiated into neuroectodermal cells. Now we will further optimize our in vitro protocol for differentiation into NSCs and motor neurons, determining the phenotypes of differentiated cells in vitro by genomic, proteomic, and functional analyses. We will define optimal NSC and motor neuron transplantation regimens, including immunosuppression protocols into SMARD1 transgenic mice. We will determine also the survival, differentiation, and function of NSCs and motor neurons after transplantation into a mouse model of SMARD1. We will investigate the ability of donor-derived motor neurons to reach the periphery and form functionally active neuromuscular junctions after administration of small molecules that promote axonal elongation. We will determine also the capacity of transplanted cells to improve muscle strength and survival after transplantation. Our goal is to examine bi-directional cellular and molecular interactions between transplanted donor-derived motor neurons and host cells to identify mechanisms that underlie the modulation of disease pathways other than cell replacement. This study will contribute to advances in cell-mediated approaches for treating SMARD1 and other motor neuron diseases.