PT  - JOURNAL ARTICLE
AU  - Md. Suhail Alam
AU  - Bruce Cooper
AU  - Kasturi Haldar
TI  - Tolerance of chronic HDACi-administration used for treatment of neurological and visceral disease including lung pathogenesis
AID  - 10.1101/191635
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 191635
4099  - http://biorxiv.org/content/early/2017/09/20/191635.short
4100  - http://biorxiv.org/content/early/2017/09/20/191635.full
AB  - Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use in 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) 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 it’s 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 for 8-10 months was not detrimental to brain or neuromuscular functions of healthy mice, based on quantitative analyses of major Purkinje neurons in the cerebellum, inflammation in the hippocampus and symptoms of progressive neurocognitive/muscular disease. The TCF was also not injurious to lung tissue but rather improved delivery of Vo to lungs and reduced accumulation of foamy macrophages in Npc1nmf164 mice. Together these data support feasibility of tolerable, chronic administration of an HDACi formulation to treat brain and systemic disease including lung pathology, a frequent cause of death in NPC and possibly other neurological diseases.