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

Hum Mol Genet. 2014 Nov 15;23(22):6022-33. doi: 10.1093/hmg/ddu331. Epub 2014 Jun 25.


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.

Publication types

  • Clinical Trial

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Adolescent
  • Animals
  • Biomarkers / blood
  • Child
  • Cholesterol / blood*
  • Disease Models, Animal
  • Drug Monitoring / methods
  • Female
  • Homeostasis
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Niemann-Pick Disease, Type C / blood
  • Niemann-Pick Disease, Type C / drug therapy*
  • Young Adult
  • beta-Cyclodextrins / administration & dosage*


  • Biomarkers
  • beta-Cyclodextrins
  • 2-Hydroxypropyl-beta-cyclodextrin
  • Cholesterol