Niemann-Pick C (NPC) is a rare, neurodegenerative, lipid storage disease. Approximately 95% of the disease is caused by mutations in NPC1, a late endosomal/lysosomal (LE/Ly) membrane protein that functions in export of lipoprotein-derived cholesterol. Affected individuals typically present in early childhood with ataxia and progressive impairment of motor and intellectual function, and usually die in adolescence. There are currently no FDA-approved therapies for this fatal neurodegenerative disorder. Recently, we found that treatment of human NPC1 mutant cells with certain histone deacetylase inhibitors (HDACi), including Vorinostat (SAHA, Zolinza(tm)), leads to clearance of excess cholesterol and other lipids from the LE/Ly, and it corrects the overall defect in cholesterol regulation. In other unpublished work, we found that 60 of the 80 NPC1 mutants examined show significant cholesterol clearance upon treatment with the HDACi, indicating the majority or NPC1 patients may benefit from HDACi therapy. Vorinostat is an excellent candidate for clinical testing as an NPC1 therapeutic because it is orally-available, CNS-penetrant, and FDA-approved. The goal of our study is to examine Vorinostat in a Phase 1 clinical trial for the treatment of NPC1 disease. To meet this objective, we will develop a Phase 1, first-in-human, open-label, single-center, dose escalation study of Vorinostat in late adolescents and adults with NPC1 disease to establish the safety of Vorinostat for treatment of this disorder. 12 NPC1 patients (18 years and older) will be recruited for the study. Study participants will initially be dosed with 200 mg po daily for three months, followed by dose escalation to 400 mg po daily for three months. Plasma and CSF pharmacokinetics will be obtained, toxicity monitored, and clinical assessments performed. We will further evaluate the utility of peripheral and CSF disease biomarkers to guide therapy in the Phase 1 Vorinostat dose-escalation study. The primary outcome measure will be CSF 3?,5?,3?- cholesten-triol, a cholesterol oxidation product that is specifically elevated in NPC1 disease and decreases in response to alleviation of neuronal cholesterol storage. Secondary outcome measures will include plasma 24(S)-hydroxycholesterol, a CNS-specific oxysterol that is elevated following correction of the neuronal cholesterol trafficking defect;CSF sphingolipid markers;CSF proteins (e.g., Calbindin D and FABP3);and histone acetylation and NPC1 protein levels in circulating mononuclear cells. These outcome measures can potentially serve as surrogate outcome measures in future Phase 2/3 HDACi trials.

Public Health Relevance

Niemann-Pick C is rare neurodegenerative, cholesterol storage disease for which there are no FDA-approved therapies. Treatment of human NPC1 mutant cells with a class of compounds known as histone deacetylase inhibitors (HDACi) stabilizes mutant NPC1 proteins and leads to clearance of excess cholesterol from lysosomes. Based on our preliminary data, it is anticipated that the majority of NPC1 patients could benefit from HDACi treatment. The goal of our study is to establish the safety of Vorinostat, an FDA-approved HDACi, in a Phase 1 clinical trial for treatment of NPC1 disease. We will also examine the utility of biochemical disease biomarkers to guide drug therapy. This trial will be conducted at the NIH Clinical Center and is a collaboration of extramural and intramural NPC disease experts. Results from this study will lay the foundation for future clinical trials to assess the effectiveness of Vorinostat in slowing disease progression, and may lead to the first FDA-approved drug for the treatment of this devastating disorder.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-BDCN-L (60))
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Oster-Granite, Mary Lou
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Washington University
Anatomy/Cell Biology
Schools of Medicine
Saint Louis
United States
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Pipalia, Nina H; Subramanian, Kanagaraj; Mao, Shu et al. (2017) Histone deacetylase inhibitors correct the cholesterol storage defect in most Niemann-Pick C1 mutant cells. J Lipid Res 58:695-708