You are currently viewing the abstract.
View Full TextLog in to view the full text
AAAS login provides access to Science for AAAS members, and access to other journals in the Science family to users who have purchased individual subscriptions.
Register for free to read this article
As a service to the community, this article is available for free. Existing users log in.
More options
Download and print this article for your personal scholarly, research, and educational use.
Buy a single issue of Science for just $15 USD.
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.
Abstract
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.
- Copyright © 2016, American Association for the Advancement of Science
