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. The goal of the study 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. The efficacy of TCF was attributable to enhanced HPβCD PK and independent of NPC1 protein expression. It was concluded that although HDACi effectively reduce cholesterol storage in NPC1-deficient cells, HDACi are ineffective in vivo in Npc1 mice.
Davidson J, Molitor E, Moores S, Gale SE, Subramanian K, Jiang X, Sidhu R, Kell P, Zhang J, Fujiwara H, Davidson C, Helquist P, Melancon BJ, Grigalunas M, Liu G, Salahi F, Wiest O, Xu X, Porter FD, Pipalia NH, Cruz DL, Holson EB, Schaffer JE, Walkley SU, Maxfield FR, Ory DS: 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.