Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model
Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model
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DOI：
10.1126/scitranslmed.aad9407
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发表时间：
2016-02-17
影响因子：
17.1
通讯作者：
Haldar, Kasturi
中科院分区：
文献类型：
--
作者：
Alam, Md Suhail;Getz, Michelle;Haldar, Kasturi
组蛋白去乙酰化酶抑制剂（HDACi）已被批准用于治疗罕见癌症，并作为神经退行性疾病的潜在疗法而受到关注。我们评估了一种三联制剂（TCF），该制剂包括泛hdaci vorinostat、笼化剂2-羟丙基-b-环糊精（HPBCD）和聚乙二醇（PEG），用于治疗尼曼-皮克C型（NPC）疾病小鼠模型（Npc1（nmf164）小鼠），这是一种难以治疗的小脑疾病。伏立诺他单独在培养的Npc1（nmf164）小鼠原代细胞中显示活性，但不能提高动物存活率。然而，每周一次的低剂量腹腔注射含有伏立诺他的TCF增加了小鼠大脑中的组蛋白乙酰化，保存了神经突和浦肯野细胞，延迟了神经变性症状，并将小鼠的寿命从4个月延长到近9个月。我们证明，TCF提高了HDACi穿过血脑屏障的能力，即使长期使用也没有毒性。此外，TCF能够减少剂量，这一直是hdac治疗的主要挑战。TCF在小鼠模型中同时治疗尼曼-匹克C型病的神经退行性和全身性症状。
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-b-cyclodextrin (HPBCD), and polyethylene glycol (PEG) for treating a mouse model (the Npc1(nmf164) mouse) of Niemann-Pick type C (NPC) disease, a difficult-to-treat cerebellar disorder. Vorinostat alone showed activity in cultured primary cells derived from Npc1(nmf164) 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.