Abstract
Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use to treat neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination formulation (TCF) of the pan HDACi vorinostat (Vo), 2-hydroxypropyl-beta-cyclodextrin (HPBCD) and polyethylene glycol (PEG) 400 improves pharmacokinetic exposure and entry of Vo into the brain. TCF treatment significantly delayed both neurodegeneration and death in the Npc1nmf164 murine model of Niemann-Pick Type C (NPC) disease. The TCF induces no metabolic toxicity, but its risk to normal brain functions and potential utility in treating lung disease, a major NPC clinical complication, remain unknown. Here we report that TCF administered in healthy mice for 8–10 months was not detrimental to the brain or neuromuscular functions based on quantitative analyses of Purkinje neurons, neuroinflammation, neurocognitive/muscular disease symptom progression, cerebellar/hippocampal nerve fiber-staining, and Hdac gene-expression. The TCF also improved delivery of Vo to lungs and reduced accumulation of foamy macrophages in Npc1nmf164 mice, with no injury. Together, these data support feasibility of tolerable, chronic administration of an HDACi formulation that treats murine NPC neurological disease and lung pathology, a frequent cause of death in this and possibly additional disorders.
Highlights
Histone deacetylase inhibitors (HDACi) are emerging therapeutics for a broad range of diseases including cancer and neurodegeneration[1,2,3,4]
It has been hypothesized that long-term HDACi treatment may adversely affect the brain
Since Vo from the triple combination formulation (TCF) peaked at 30 minutes post injection and was rapidly cleared from the brain and plasma[10], we hypothesized that epigenetic modulation associated with a transient block of HDAC3 may be well tolerated and benefit Niemann-Pick Type C (NPC)-diseased animals
Summary
Histone deacetylase inhibitors (HDACi) are emerging therapeutics for a broad range of diseases including cancer and neurodegeneration[1,2,3,4]. Systemic delivery is needed to improve liver and other visceral organs but inexplicably, HPBCD is excluded from lung[29,30] and it is of little benefit to end-stage, advanced and frequently fatal bronchial disease Arimoclomol is another emergent therapy for NPC31, but its benefit for systemic disease especially in the treatment of lung inflammatory disease remains unknown. While HPBCD reduces systemic inflammation[10,24,29], it is excluded from lungs[29,30] and whether the TCF promotes Vo delivery and therapeutic action in lungs remains unidentified Our findings on these points advance the pre-clinical development of a new HDACi therapeutic strategy to treat NPC and other difficult-to-treat disorders that may benefit from epigenetic therapy
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