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

Jessica Davidson, Elizabeth Molitor, Samantha Moores, Sarah E. Gale, Kanagaraj Subramanian, Xuntian Jiang, Rohini Sidhu, Pamela Kell, J. Zhang, Hideji Fujiwara, Cristin Davidson, Paul Helquist, Bruce J. Melancon, Michael Grigalunas, Gang Liu, Farbod Salahi, Olaf Wiest, Xin Xu, Forbes D. Porter, Nina H. PipaliaDana L. Cruz, Edward B. Holson, Jean E. Schaffer, Steven U. Walkley, Frederick R. Maxfield, Daniel S. Ory

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1545-1561
Number of pages17
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Issue number10
StatePublished - Oct 2019


  • Cholesterol
  • Cyclodextrin
  • Histone deacetylase inhibitors
  • NPC1 protein
  • Neurodegeneration
  • Niemann-Pick C

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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