@article{27eb8dee340e4c5fb0b3aded31a2ccca,
title = "2-Hydroxypropyl-β-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease",
abstract = "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",
author = "Jessica Davidson and Elizabeth Molitor and Samantha Moores and Gale, {Sarah E.} and Kanagaraj Subramanian and Xuntian Jiang and Rohini Sidhu and Pamela Kell and J. Zhang and Hideji Fujiwara and Cristin Davidson and Paul Helquist and Melancon, {Bruce J.} and Michael Grigalunas and Gang Liu and Farbod Salahi and Olaf Wiest and Xin Xu and Porter, {Forbes D.} and Pipalia, {Nina H.} and Cruz, {Dana L.} and Holson, {Edward B.} and Schaffer, {Jean E.} and Walkley, {Steven U.} and Maxfield, {Frederick R.} and Ory, {Daniel S.}",
note = "Funding Information: Funding : This work was supported by grants from the Ara Parseghian Medical Research Foundation (P.H., O.W., G.L., F.S., B.J.M., D.S.O., S.U.W. and F.R.M), NIH Grant R01 NS092653 (P.H., O.W., D.S.O., S.U.W. and F.R.M), and NSF grants CHE-1058075 and CHE-1565669 (M.G.). This study was also supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F.D.P.). This work was performed in the Metabolomics Facility at Washington University (NIH P30 DK020579 and NIH P30 DK056341). Author contributions : J.D., E.Q., S.M., J.Z. and S.E.G. performed the mouse studies. X.J., R.S., J.Z., P.K. and H.F. performed mass spectrometry experiments and analyzed and interpreted the data. X.X. performed the PK analyses. C.D. and S.U.W. performed histopathology and analyzed the data. M.G., G.L. and F.S. performed the syntheses of compounds and internal standards under the direction of P.H. and B.J.M. K.S. and N.P. assisted with analysis of histone acetylation. O.W., P.H., E.H., F.D.P., S.U.W., F.R.M., J.E.S. and D.S.O. planned the studies and wrote the manuscript. Competing interests : The authors report no competing interests. Data and materials availability : All reasonable requests for chemical compounds and assay protocols described in this work will be fulfilled via an MTA or licensing agreements with the University of Notre Dame or Washington University. Funding Information: Funding: This work was supported by grants from the Ara Parseghian Medical Research Foundation (P.H. O.W. G.L. F.S. B.J.M. D.S.O. S.U.W. and F.R.M), NIH Grant R01 NS092653 (P.H. O.W. D.S.O. S.U.W. and F.R.M), and NSF grants CHE-1058075 and CHE-1565669 (M.G.). This study was also supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F.D.P.). This work was performed in the Metabolomics Facility at Washington University (NIH P30 DK020579 and NIH P30 DK056341). Author contributions: J.D. E.Q. S.M. J.Z. and S.E.G. performed the mouse studies. X.J. R.S. J.Z. P.K. and H.F. performed mass spectrometry experiments and analyzed and interpreted the data. X.X. performed the PK analyses. C.D. and S.U.W. performed histopathology and analyzed the data. M.G. G.L. and F.S. performed the syntheses of compounds and internal standards under the direction of P.H. and B.J.M. K.S. and N.P. assisted with analysis of histone acetylation. O.W. P.H. E.H. F.D.P. S.U.W. F.R.M. J.E.S. and D.S.O. planned the studies and wrote the manuscript. Competing interests: The authors report no competing interests. Data and materials availability: All reasonable requests for chemical compounds and assay protocols described in this work will be fulfilled via an MTA or licensing agreements with the University of Notre Dame or Washington University. Publisher Copyright: {\textcopyright} 2019 Elsevier B.V.",
year = "2019",
month = oct,
doi = "10.1016/j.bbalip.2019.04.011",
language = "English",
volume = "1864",
pages = "1545--1561",
journal = "Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids",
issn = "1388-1981",
number = "10",
}