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2-hydroxypropyl-β-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 Disease
- Source :
- Biochim Biophys Acta Mol Cell Biol Lipids
- Publication Year :
- 2019
-
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.
- Subjects :
- 0301 basic medicine
Male
congenital, hereditary, and neonatal diseases and abnormalities
medicine.drug_class
Pharmacology
Article
Polyethylene Glycols
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Pharmacokinetics
In vivo
Niemann-Pick C1 Protein
hemic and lymphatic diseases
medicine
Animals
Molecular Biology
Vorinostat
Cells, Cultured
Mice, Inbred BALB C
Chemistry
Cholesterol
Histone deacetylase inhibitor
Intracellular Signaling Peptides and Proteins
nutritional and metabolic diseases
Niemann-Pick Disease, Type C
Cell Biology
2-Hydroxypropyl-beta-cyclodextrin
Histone Deacetylase Inhibitors
Drug Combinations
030104 developmental biology
Mechanism of action
lipids (amino acids, peptides, and proteins)
medicine.symptom
NPC1
Cholesterol storage
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Biochim Biophys Acta Mol Cell Biol Lipids
- Accession number :
- edsair.doi.dedup.....9e8a6def6a85a87eb028dfe857c0d033