Isogenic Patient-Derived Organoids Reveal Early Neurodevelopmental Defects in Spinal Muscular Atrophy Initiation

Whether neurodevelopmental defects underlie selective neuronal death in neurodegeneration is an intriguing hypothesis only recently explored. To test it, we focused on spinal muscular atrophy (SMA), a neuromuscular disorder caused by reduced SMN protein levels resulting in progressive spinal motor neuron (MN) loss and muscle wasting. Utilizing the first isogenic patient-derived induced pluripotent stem cell model and a spinal cord organoid (SCO) system that we generated, we report that correcting SMN2 into SMN1 is insufficient to revert all identified neurodevelopmental defects. Specifically, SMA SCOs exhibited abnormal morphodynamics and severely reduced expression of early neural progenitor and MN markers. Furthermore, longitudinal single-cell RNA-sequencing revealed marked defects in neural stem cell specification and ultimately, a reduced number of MNs, in favor of neuromesodermal progenitors and muscle cells. Our findings indicate that neurodevelopmental defects might trigger MN degeneration in SMA and raise the relevant clinical implication that postnatal SMN-increasing treatments might not fully amend SMA pathology.