Cyclodextrin for Niemann-Pick Type C1 Disease

尼曼-匹克C1型（NPC 1）是一种常染色体隐性遗传的神经退行性疾病，发生率为1/120，000活产婴儿。大约95%的病例是由NPC 1基因突变引起的，其余5%是由NPC 2基因突变引起的。产生有缺陷的NPC 1蛋白（一种胆固醇运输蛋白）的突变导致未酯化胆固醇和其他脂质在溶酶体中积累。该病的表现包括新生儿黄疸、脾肿大、共济失调和进行性神经退行性运动和智力功能障碍。最常见的是，症状发生在幼儿期，导致十年内死亡。 目前，FDA尚未批准用于这种渐进性致命神经退行性疾病的疗法。HPBCD已被证明可以减少胆固醇和鞘脂储存，并延长两种类型的尼曼-匹克C1型动物模型的生存期。该项目的目标是提供所需的分析和临床工具，以建立安全有效的给药方案，用于治疗人类受试者的HPBCD。 TRND建立了一个由来自9个不同组织的学术和工业科学家组成的跨学科项目小组，并不断收到患者倡导团体的意见，以最有效地完成HPBCD的临床评价。TRND的科学家进行了必要的动物毒理学研究，以向FDA提交研究性新药（IND）申请，并帮助支持生物标志物研究。TRND于2012年11月提供监管支持，以获得FDA的研究性新药（IND）申请，并于2013年1月在美国国立卫生研究院（NIH）临床中心开始首次人体临床试验。这些临床研究目前正在进行中。

Niemann-Pick type C1 (NPC1) is an autosomal recessive, neurodegenerative disease with a frequency of one in 120,000 live births. Approximately 95 percent of cases are caused by mutations of the NPC1 gene, and the remaining 5 percent are caused by mutations in the NPC2 gene. Mutations that produce defective NPC1 protein, a cholesterol trafficking protein, lead to accumulation of unesterified cholesterol and other lipids in lysosomes. Manifestations of the disease include neonatal jaundice, splenomegaly, ataxia and progressive neurodegenerative impairment of motor and intellectual function. Most often, the onset of symptoms occurs in early childhood, leading to death within a decade. Currently, no therapies have been approved by the FDA for this progressively fatal neurodegenerative disease. HPBCD has been shown to reduce both cholesterol and sphingolipid storage and to prolong survival in two types of Niemann-Pick type C1 animal models. The goal of this project is to provide the analytical and clinical tools needed to establish safe and effective dosing regimens for treatment of human subjects with HPBCD. TRND established an interdisciplinary project team of academic and industrial scientists from nine different organizations and received ongoing input from patient advocacy groups in order to accomplish the clinical evaluation of HPBCD most efficiently. TRND scientists conducted the animal toxicology studies necessary to file an Investigational New Drug (IND) Application with the FDA and helped support biomarker studies. TRND provided regulatory support to achieve clearance of the Investigational New Drug (IND) Application with the FDA in November 2012, and first-in-human clinical trials began in January 2013 at the National Institutes of Health (NIH) Clinical Center. These clinical studies are currently ongoing.