Histone Deacetylase Inhibitors for Treatment of Niemann-Pick C1 Disease

 描述（由申请方提供）：尼曼匹克C病是一种罕见的神经退行性脂质沉积疾病。大约95%的疾病是由NPC 1突变引起的，NPC 1是一种晚期内体膜蛋白，其功能是输出脂蛋白衍生的胆固醇。最普遍的NPC 1突变I1061 T产生错误折叠并迅速降解的蛋白质。组蛋白脱乙酰酶抑制剂（HDACi）最近已被证明可以减少胆固醇和其他脂质的积累，发现在患者细胞携带NPC 1 I1061 T和其他突变。这种有益的作用与减少内质网相关的降解和增强的突变NPC 1蛋白向晚期内体和溶酶体的递送有关。随着我们实验室最近产生的人源化小鼠模型，其中I1061 T突变敲入鼠NPC 1基因座，有可能检查HDACi对NPC 1体内稳定性的影响。我们假设在NPC 1疾病的NPC 1 I1061 T敲入模型中用HDACi治疗将增加突变型NPC 1 I1061 T蛋白的水平，减缓神经变性的进展并延长存活。HDACi治疗NPC 1疾病的治疗潜力正在通过涉及制药合作伙伴的合作和涉及NIH（NICHD/NCATS），Weill Cornell医学院，圣母大学，阿尔伯特爱因斯坦医学院和华盛顿大学的研究人员的HDACi合作进行探索，沿着Ara Parseghian医学研究基金会。该提案的目标是使用基于细胞的筛选来鉴定口服可用的CNS渗透HDAC选择性化合物;在NPC 1 I1061 T敲入模型中体内评估候选HDACi化合物;以及开发用于在临床试验中测试HDACi的有效治疗方案。的拟定 进一步的体内研究将为未来人体试验中的初始给药方案和生物标志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.