Histone Deacetylase Inhibitors for Treatment of Niemann-Pick C1 Disease

? DESCRIPTION (provided by applicant): Niemann Pick C disease is a rare, neurodegenerative, lipid storage disorder. Approximately 95% of the disease is caused by mutations in NPC1, a late endosomal membrane protein that functions in export of lipoprotein-derived cholesterol. The most prevalent NPC1 mutation, I1061T, produces a protein that is misfolded and rapidly degraded. Histone deacetylase inhibitors (HDACi) recently have been shown to reduce the accumulation of cholesterol and other lipids found in patient cells harboring the NPC1I1061T and other mutations. This beneficial effect is associated with decreased endoplasmic reticulum-associated degradation and enhanced delivery of the mutant NPC1 proteins to late endosomes and lysosomes. With the recent generation in our laboratory of a humanized mouse model in which the I1061T mutation knocked into the murine NPC1 locus, it is possible to examine the effect of HDACi on NPC1 stability in vivo. We hypothesize that treatment with an HDACi in the NPC1I1061T knockin model of NPC1 disease will increase levels of the mutant NPC1I1061T protein, slowing progression of neurodegeneration and prolonging survival. The therapeutic potential of HDACi for treatment of NPC1 disease is being explored in through a collaboration involving pharmaceutical partners and an HDACi collaborative involving investigators from NIH (NICHD/NCATS), Weill Cornell Medical College, University of Notre Dame, Albert Einstein College of Medicine, and Washington University, along with the Ara Parseghian Medical Research Foundation. The goals of this proposal are to identify orally-available, CNS-penetrant HDAC-selective compounds using cell-based screens; to evaluate in vivo in the NPC1I1061T knockin model candidate HDACi compounds; and to develop effective therapeutic regimens for testing of the HDACi in clinical trials. The proposed in vivo studies further will provide valuable data for initial dosing protocols and biomarker monitoring in future human trials.