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Niemann–Pick C1 (NPC1) disease is a rare, neurodegenerative lysosomal cholesterol storage disorder, typified by progressive cognitive and motor function impairment. Affected individuals usually succumb to the disease in adolescence. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) has emerged as a promising intervention that reduces lipid storage and prolongs survival in NPC1 disease animal models. A barrier to the development of HP-β-CD and other treatments for NPC disease has been the lack of validated biochemical measures to evaluate efficacy. Here we explored whether cholesterol homeostatic responses resulting from HP-β-CD-mediated redistribution of sequestered lysosomal cholesterol could provide biomarkers to monitor treatment. Upon direct CNS delivery of HP-β-CD, we found increases in plasma 24( S )-HC in two independent NPC1 disease animal models, findings that were confirmed in human NPC1 subjects receiving HP-β-CD. Since circulating 24( S )-HC is almost exclusively CNS-derived, the increase in plasma 24( S )-HC provides a peripheral, non-invasive measure of the CNS effect of HP-β-CD. Our findings suggest that plasma 24( S )-HC, along with the other cholesterol-derived markers examined in this study, can serve as biomarkers that will accelerate development of therapeutics for NPC1 disease.

Cholesterol homeostatic responses provide biomarkers for monitoring treatment for the neurodegenerative disease Niemann–Pick C1 (NPC1)