Histone Deacetylase Inhibitors for Treatment of Niemann-Pick C1 Disease

组蛋白脱乙酰酶抑制剂用于治疗 Niemann-Pick C1 病

• 批准号: 9333438
• 负责人: Frederick R. Maxfield
• 金额: $ 49.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333438
• 关键词: Address; Adolescence; Affect; Alpha Cell; Bioavailable; Biological Assay; Biological Availability; Biological Markers; Blood - brain barrier anatomy; Brain; Cells; Chemicals; Child; Cholesterol; Clinical; Clinical Research; Clinical Trials; Collaborations; Combined Modality Therapy; Communities; Complement; Computer Simulation; Computer software; Cyclodextrins; Data; Disease; Disease model; Dose; Drug Kinetics; Effectiveness; Embryo; Endoplasmic Reticulum; Equilibrium; FDA approved; Fibroblasts; Foundations; Future; Gene Expression; Generations; Goals; Growth; Half-Life; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Injectable; Knock-in; Knock-in Mouse; Laboratories; Libraries; Lipids; Lipoproteins; Liver; Lysosomes; Maximum Tolerated Dose; Measures; Medical Research; Medicine; Membrane Proteins; Miglustat; Modeling; Monitor; Mononuclear; Mus; Mutation; NPC1 gene; National Institute of Child Health and Human Development; Nerve Degeneration; Neurodegenerative Disorders; Oral; Patients; Penetration; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phenotype; Plasma; Program Development; Property; Protein Acetylation; Proteins; Protocols documentation; Regimen; Research Personnel; Specificity; Stable Isotope Labeling; Symptoms; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Universities; Vorinostat; Washington; Western Blotting; base; brain tissue; cellular pathology; college; design; drug candidate; drug development; early childhood; humanized mouse; improved; in vivo; late endosome; medical schools; misfolded protein; motor impairment; mouse model; mutant; neuroprotection; novel drug class; phase 1 study; protein function; public health relevance; screening; tandem mass spectrometry; treatment trial

 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.

 描述（由适用提供）：Niemann Pick C疾病是一种罕见的神经退行性，脂质储存障碍。大约95％的疾病是由NPC1突变引起的，NPC1是一种晚期内体膜蛋白，可在脂蛋白衍生的胆固醇中发出。最普遍的NPC1突变I1061T产生的蛋白质被错误折叠并迅速降解。最近已证明组蛋白脱乙酰基酶抑制剂（HDACI）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。这种有益的作用与改善内质网相关降解以及突变NPC1蛋白向晚期内体和溶酶体的递送有关。随着我们在实验室的近代人源化小鼠模型中，I1061T突变撞到了鼠NPC1基因座中，可以检查HDACI对体内NPC1稳定性的影响。我们假设在NPC1I1061T敲击NPC1疾病中用HDACI治疗将增加突变体NPC1I1061T蛋白的水平，从而减慢神经退行性的进展并延长生存率。 HDACI治疗NPC1疾病的治疗潜力正在通过涉及药品合作伙伴的合作以及NIH（NICHD/NCATS），Weill Cornell医学院，Notre Dame，Albert Einstein College，Medicine of Medicine和Washington University以及ARA PARSEGHIAN PARSEGHIAN FUNDICY的HDACI合作参与研究人员。该提案的目标是使用基于细胞的筛选来识别口服可用的CNS-PENETRANT HDAC选择化合物；评估NPC1I1061T敲击模型候选HDACI化合物中的体内；并开发有效的治疗方案，用于在临床试验中测试HDACI。提出的 Vivo研究将进一步提供有价值的数据，以在未来的人类试验中为初始给药方案和生物标志物监测提供有价值的数据。