Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells

Niemann-Pick type C (NPC) disease is a fatal inherited lipid storage disorder causing severe neurodegeneration and liver dysfunction with only limited treatment options for patients. Loss of NPC1 function causes defects in cholesterol metabolism and has recently been implicated in deregulation of autophagy. Here, we report the generation of isogenic pairs of NPC patient-specific induced pluripotent stem cells (iPSCs) using transcription activator-like effector nucleases (TALENs). We observed decreased cell viability, cholesterol accumulation, and dysfunctional autophagic flux in NPC1-deficient human hepatic and neural cells. Genetic correction of a disease-causing mutation rescued these defects and directly linked NPC1 protein function to impaired cholesterol metabolism and autophagy. Screening for autophagy-inducing compounds in disease-affected human cells showed cell type specificity. Carbamazepine was found to be cytoprotective and effective in restoring the autophagy defects in both NPC1-deficient hepatic and neuronal cells and therefore may be a promising treatment option with overall benefit for NPC disease. [Display omitted] •Generation of Niemann-Pick type C (NPC) disease patient-specific iPSCs•NPC1 hepatic and neuronal cells show defects in cholesterol and autophagic flux•TALEN-mediated genetic correction rescues the cholesterol and autophagy defects•Autophagy inducers can restore functional autophagy and increase cell viability iPSCs are valuable for studying human diseases in affected cell types and screening for therapeutic compounds. Here, Jaenisch and colleagues show that genetic correction of a disease-causing mutation in Niemann-Pick type C iPSCs directly linked NPC1 protein function to impaired cholesterol metabolism and autophagy. Stimulating autophagy with carbamazepine was cytoprotective in both hepatic and neural cells and therefore may be of therapeutic relevance.