Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model

See allHide authors and affiliations

Science Translational Medicine  17 Feb 2016:
Vol. 8, Issue 326, pp. 326ra23
DOI: 10.1126/scitranslmed.aad9407

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Crossing the Rubicon

Histone deacetylase inhibitors (HDACi) are a class of compounds that have shown promise for treating certain types of cancer. Because HDACi do not cross the blood-brain barrier (BBB), they cannot enter the brain and therefore are of limited value for treating neurological diseases. Now, Alam et al. have developed a new formulation that enables the FDA-approved HDACi vorinostat to cross the BBB and enter the brain tissue of mice with Niemann-Pick type C disease. The authors show that long-term treatment with the formulation improves brain function and prolongs mouse survival, suggesting that this new HDACi formulation will be of benefit for treating Niemann-Pick type C disease and perhaps other types of neurological diseases as well.


Histone deacetylase inhibitors (HDACi) are approved for treating rare cancers and are of interest as potential therapies for neurodegenerative disorders. We evaluated a triple combination formulation (TCF) comprising the pan-HDACi vorinostat, the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD), and polyethylene glycol (PEG) for treating a mouse model (the Npc1nmf164 mouse) of Niemann-Pick type C (NPC) disease, a difficult-to-treat cerebellar disorder. Vorinostat alone showed activity in cultured primary cells derived from Npc1nmf164 mice but did not improve animal survival. However, low-dose, once-weekly intraperitoneal injections of the TCF containing vorinostat increased histone acetylation in the mouse brain, preserved neurites and Purkinje cells, delayed symptoms of neurodegeneration, and extended mouse life span from 4 to almost 9 months. We demonstrate that the TCF boosted the ability of HDACi to cross the blood-brain barrier and was not toxic even when used long term. Further, the TCF enabled dose reduction, which has been a major challenge in HDACi therapy. TCF simultaneously treats neurodegenerative and systemic symptoms of Niemann-Pick type C disease in a mouse model.

View Full Text

Stay Connected to Science Translational Medicine