Generation and characterization of human iPSC-derived NPC1I1061T/I10161T i3Neurons as a model for NPC1 disease

This manuscript describes the generation of an inducible pluripotent stem cell (iPSC) line expressing a mutant form of NPC1. This variant, NPC1(I1061T/I1061T), represents a common pathogenic variant of NPC1 in NPC1 affected individuals. Upon differentiation of the iPSCs into i3Neurons, we characterized the cellular phenotype with respect to gycosylation of NPC1, accumulation of free cholesterol, and response to known therapeutics. The results demonstrate that this cell line exhibits the expected characteristics of the NPC1(I1061/I1061T) mutant protein resulting in an NPC1 disease phenotype in these cells. This new cell line can be used as a neuronal model of Niemann-Pick disease, type C1.