Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no effective treatments. Motor neurons (MNs) derived from ALS patients’ induced pluripotent stem cells (iPSCs) can reflect some ALS cellular pathologies. However, during reprogramming, iPSCs are reset to an embryonic state and conceal age-associated pathologies. We developed a method to turn human blood into induced neural stem cells (iNSCs) without going through a pluripotent state. iNSC are amenable for single cell passaging and precise genome editing that allowed us to engineer an TARDBP-Q331K mutation. We have generated iNSCs and isogenic iPSC lines from several donors with different ages, including patients with SOD1 and C9orf72 mutations. I will present comparisons of iNSC with iPSC-derived NSCs using epigenetic clocks and transcriptome analyses and ongoing efforts to model ALS pathogenesis in cell and organoids models. We aim to develop more authentic models to capture ALS pathology to evaluate pharmacological and genetic interventions.
