. Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model. Sci Transl Med. 2016 Feb 17;8(326):326ra23. PubMed.


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  1. This strikes me as a creative way to deliver a potent class of therapeutics for a host of neurodegenerative diseases, exactly as the authors suggest. HDAC inhibitors have been a drug discovery/development class of intense scrutiny for many years and, from the little I know, have not shown enough promise in the CNS arena to generate much in the way of continued enthusiasm and investment. It will be interesting to see if this finding opens doors.

    View all comments by Pierre Tariot
  2. We thank Dr. Tariot for his comment. Our strategy was to enable safe but effective chronic systemic administration, and increase brain penetration of the HDACi. Complexing vorinostat with the GRAS caging agent (cyclodextrin) achieved all of the above by increasing the PK of vorinostat, allowing dose reduction and improved penetration into the brain and reduction of overall inflammation (systemically largely due to cyclodextrin). The rest period is also important to enable the HDAC activity required for brain function. In this context, the periodic, transient, low levels of target (and other) gene expression achieved is very beneficial in a monogenetic disorder and may also translate to polygenetic disorders (since both pan and specific HDACi have broad target range).

    What we observe in mice seems to be mimicked in preliminary studies in outbred rats, so we are hopeful about planned studies in humans.

    View all comments by Kasturi Haldar
  3. This study puts forth a novel strategy to treat the rare neurodegenerative disorder Niemann-Pick type C disease (NPC). This method utilizes a triple combination formulation of the HDAC inhibitor vorinostat, the lipid chelator 2-hydroxypropyl-β-cyclodextrin (HPBCD), and polyethylene glycol (PEG) to simultaneously treat neurological and systemic disease. While HPBCD and PEG alone have been shown to decrease neuroinflammation and reduce blood-brain barrier inflammation, respectively, in combination with vorinostat, the diverse symptoms associated with a mouse model of NPC are significantly improved. Although the exact mechanism is unclear, this study suggests that targeting both systemic inflammation and transcriptional deregulation may serve as a powerful strategy for treating neurodegenerative diseases.

    View all comments by Li-Huei Tsai
  4. We found that administration as a formulation (rather than as separate components at the same time) and improving the plasma and brain exposure of the HDACi were important to treat neurological disease. In addition, the amplitude of transcriptional deregulation was kept deliberately small to enable chronic administration. Nonetheless, this increased NPC1 protein levels far greater than transcript levels, probably due to effects through chaperones and other factors. But yes, reducing inflammation at the same time was key.

    View all comments by Kasturi Haldar

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