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2-Hydroxypropyl-?-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 (HP?CD) 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/HP?CD/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 HP?CD 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.

SUBMITTER: Davidson J

PROVIDER: S-EPMC6679735 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Davidson Jessica J Molitor Elizabeth E Moores Samantha S Gale Sarah E SE Subramanian Kanagaraj K Jiang Xuntian X Sidhu Rohini R Kell Pamela P Zhang Jesse J Fujiwara Hideji H Davidson Cristin C Helquist Paul P Melancon Bruce J BJ Grigalunas Michael M Liu Gang G Salahi Farbod F Wiest Olaf O Xu Xin X Porter Forbes D FD Pipalia Nina H NH Cruz Dana L DL Holson Edward B EB Schaffer Jean E JE Walkley Steven U SU Maxfield Frederick R FR Ory Daniel S DS

Biochimica et biophysica acta. Molecular and cell biology of lipids 20190430 10

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 ...[more]

PMID: 31051283

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Project description:2-Hydroxypropyl-beta-cyclodextrin (HPβCD) has gained recent attention as a potential therapeutic intervention in the treatment of the rare autosomal-recessive, neurodegenerative lysosomal storage disorder Niemann-Pick Disease Type C1 (NPC1). Notably, HPβCD formulations are not comprised of a single molecular species, but instead are complex mixtures of species with differing degrees of hydroxypropylation of the cyclodextrin ring. The degree of substitution is a critical aspect of the complex mixture as it influences binding to other molecules and thus could potentially modulate biological effects. VTS-270 (Kleptose HPB) and Trappsol® Cyclo™ are HPβCD products under investigation as novel treatments for NPC1. The purpose of the present work is to compare these two different products; analyses were based on ion distribution and abundance profiles using mass spectrometry methodology as a means for assessing key molecular distinctions between products. The method incorporated electrospray ionization and analysis with a linear low-field ion mobility quadrupole time-of-flight instrument. We observed that the number of hydroxypropyl groups (the degrees of substitution) are substantially different between the two products and greater in Trappsol Cyclo than in VTS-270. The principal ions of both samples are ammonium adducts. Isotope clusters for each of the major ions show doubly charged homodimers of the ammonium adducts. In addition, both products show doubly charged homodimers from adduction of both a proton and ammonium. Doubly charged heterodimers are also present, but are more intense in Trappsol Cyclo than in VTS-270. Based on the analytical differences observed between VTS-270 and Trappsol Cyclo with respect to the degree of substitution, the composition and fingerprint of the complex mixture, and the impurity profiles, these products cannot be considered to be the same; the potential biological and clinical implications of these differences are not presently known.

Dataset Information

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

Publications

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

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