2-Hydroxypropyl-β-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease

Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Oct;1864(10):1545-1561. doi: 10.1016/j.bbalip.2019.04.011. Epub 2019 Apr 30.


Niemann-Pick type C1 (NPC1) disease is a fatal neurovisceral disease for which there are no FDA approved treatments, though cyclodextrin (HPβCD) slows disease progression in preclinical models and in an early phase clinical trial. Our goal was to evaluate the mechanism of action of a previously described combination-therapy, Triple Combination Formulation (TCF) - comprised of the histone deacetylase inhibitor (HDACi) vorinostat/HPβCD/PEG - shown to prolong survival in Npc1 mice. In these studies, TCF's benefit was attributed to enhanced vorinostat pharmacokinetics (PK). Here, we show that TCF reduced lipid storage, extended lifespan, and preserved neurological function in Npc1 mice. Unexpectedly, substitution of an inactive analog for vorinostat in TCF revealed similar efficacy. We demonstrate that the efficacy of TCF was attributable to enhanced HPβCD PK and independent of NPC1 protein expression. We conclude that although HDACi effectively reduce cholesterol storage in NPC1-deficient cells, HDACi are ineffective in vivo in Npc1 mice.

Keywords: Cholesterol; Cyclodextrin; Histone deacetylase inhibitors; NPC1 protein; Neurodegeneration; Niemann-Pick C.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin / therapeutic use*
  • Animals
  • Cells, Cultured
  • Drug Combinations
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Niemann-Pick Disease, Type C / drug therapy*
  • Niemann-Pick Disease, Type C / metabolism
  • Polyethylene Glycols / therapeutic use*
  • Vorinostat / therapeutic use*


  • Drug Combinations
  • Histone Deacetylase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Npc1 protein, mouse
  • 2-Hydroxypropyl-beta-cyclodextrin
  • Polyethylene Glycols
  • Vorinostat