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Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Apr 30. pii: S1388-1981(19)30064-2. doi: 10.1016/j.bbalip.2019.04.011. [Epub ahead of print]

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

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Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, USA.
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556 5670, USA.
Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Dr., National Institutes of Health, Rockville, MD 20850, USA.
Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD 20892, USA.
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
KDac Therapeutics, Cambridge, MA 02139, USA.
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:


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.


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

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