Histone Deacetylase Inhibitors for Treatment of Niemann-Pick C1 Disease

 描述(申请人提供)：Niemann Pick C病是一种罕见的神经退行性脂肪储存障碍。大约95%的疾病是由NPC1突变引起的，NPC1是一种晚期内膜蛋白，功能是输出脂蛋白衍生的胆固醇。最普遍的NPC1突变I1061T会产生一种错误折叠并迅速降解的蛋白质。组蛋白去乙酰酶抑制剂(HDACi)最近被证明可以减少携带NPC1I1061T和其他突变的患者细胞中胆固醇和其他脂质的积累。这种有益的效果与减少内质网相关的降解和增加突变的NPC1蛋白向晚期内小体和溶酶体的递送有关。随着我们实验室最近建立了一种人源化的小鼠模型，在该模型中，I1061T突变敲入了小鼠的NPC1基因座，因此有可能在体内检测HDACi对NPC1稳定性的影响。我们假设，在NPC1I1061T敲打模型中使用HDACI治疗NPC1疾病将增加突变的NPC1I1061T蛋白的水平，减缓神经退变的进展，延长生存期。HDACi治疗NPC1疾病的潜力正在探索中，通过药物合作伙伴的合作和HDACi合作，来自NIH(NICHD/NCATS)、威尔·康奈尔医学院、圣母大学、阿尔伯特·爱因斯坦医学院、华盛顿大学和Ara ParSeghian医学研究基金会的研究人员参与。这项建议的目标是利用基于细胞的筛选来确定口服可用、中枢神经系统穿透的HDAC选择性化合物；在NPC1I1061T敲打模型候选HDACi化合物中进行体内评估；并开发有效的治疗方案，用于临床试验中的HDACi测试。建议中的 活体研究进一步将为未来人体试验中的初始剂量方案和生物标记物监测提供有价值的数据。

 DESCRIPTION (provided by applicant): Niemann Pick C disease is a rare, neurodegenerative, lipid storage disorder. Approximately 95% of the disease is caused by mutations in NPC1, a late endosomal membrane protein that functions in export of lipoprotein-derived cholesterol. The most prevalent NPC1 mutation, I1061T, produces a protein that is misfolded and rapidly degraded. Histone deacetylase inhibitors (HDACi) recently have been shown to reduce the accumulation of cholesterol and other lipids found in patient cells harboring the NPC1I1061T and other mutations. This beneficial effect is associated with decreased endoplasmic reticulum-associated degradation and enhanced delivery of the mutant NPC1 proteins to late endosomes and lysosomes. With the recent generation in our laboratory of a humanized mouse model in which the I1061T mutation knocked into the murine NPC1 locus, it is possible to examine the effect of HDACi on NPC1 stability in vivo. We hypothesize that treatment with an HDACi in the NPC1I1061T knockin model of NPC1 disease will increase levels of the mutant NPC1I1061T protein, slowing progression of neurodegeneration and prolonging survival. The therapeutic potential of HDACi for treatment of NPC1 disease is being explored in through a collaboration involving pharmaceutical partners and an HDACi collaborative involving investigators from NIH (NICHD/NCATS), Weill Cornell Medical College, University of Notre Dame, Albert Einstein College of Medicine, and Washington University, along with the Ara Parseghian Medical Research Foundation. The goals of this proposal are to identify orally-available, CNS-penetrant HDAC-selective compounds using cell-based screens; to evaluate in vivo in the NPC1I1061T knockin model candidate HDACi compounds; and to develop effective therapeutic regimens for testing of the HDACi in clinical trials. The proposed in vivo studies further will provide valuable data for initial dosing protocols and biomarker monitoring in future human trials.