Intrathecal cyclodextrin therapy of feline Niemann-Pick type C disease

描述（由申请人提供）：C型尼曼-匹克（NPC）病是一种儿童进行性神经系统疾病，其特征为痴呆、共济失调和死亡，通常发生在10岁或20岁以内。尽管鉴定了超过300种致病突变，但迄今为止成功治疗NPC疾病的疗法无效。2-羟丙基-β-环糊精（HPssCD），一种FDA指定的孤儿药（2010年5月），目前正在给予少数患有NPC疾病的儿童，这是基于皮下治疗npc 1-/-小鼠和猫的有利治疗结果数据。然而，由于患者样本量小，并且出于伦理原因无法在正常儿童中进行对照研究，因此无法在人类患者中解决药物作用和潜在毒性的机制。我们建议在猫模型中严格评估药理学、机制和毒性问题，该模型在NPC 1（2864 G-C）中具有自发发生的错义突变，该错义突变与患者中最常见的NPC疾病形式中最常见的突变和疾病进展直接相关，该疾病进展概括了在这些患者中观察到的神经病理学和生化异常。使用猫模型，我们在鞘内HPssCD给药后获得了非常令人鼓舞的结果，即疾病的临床神经学体征在至少24周龄（未治疗的猫死亡的年龄）内完全消退，然而，我们确定了对听觉系统的完全意外的剂量相关毒性作用。我们将利用我们高度创新的猫模型，通过以下目的进一步评估疾病发病机制和HPssCD的治疗效果：具体目的1。确定CSF中HPssCD浓度是否可预测NPC相关神经系统疾病的改善并产生耳毒性。具体目标2。识别神经系统疾病的敏感和预测性生物标志物，以监测疾病进展和治疗疗效，并提供发病机制的见解。具体目标3。评估脑部疾病进展和治疗疗效的非侵入性核磁共振（NMR）测量。 公共卫生相关性：为了最终开发出治疗NPC疾病的有效和安全的化合物，必须理解实验药物治疗的药理学、作用机制和毒性，并且使用该模型系统是可能的。可作为次要临床终点监测的经验证的脑疾病替代标志物的缺乏是NPC疾病临床试验的主要障碍，拟议的研究将使用适用于受影响儿童的技术在NPC疾病的猫模型中验证疾病严重程度和治疗结果的生化和成像标志物。

DESCRIPTION (provided by applicant): Niemann-Pick type C (NPC) disease is a progressive neurological disorder of children characterized by dementia, ataxia, and death typically within the first or second decade. Despite the identification of over 300 causative mutations, therapies to successfully treat NPC disease have been ineffective to date. 2- hydroxypropyl-ss-cyclodextrin (HPssCD), an FDA-designated orphan drug (May 2010), is now being administered to a small number of children with NPC disease based on favorable treatment outcome data in subcutaneously treated npc1-/- mice and cats. However, due to the small patient sample size and the inability to undertake control studies in normal children for ethical reasons, the mechanisms of drug action and potential toxicity cannot be addressed in human patients. We propose to rigorously evaluate the pharmacologic, mechanistic, and toxicity issues in the feline model which has a spontaneously-occurring missense mutation in NPC1 (2864G-C) orthologous to the most common mutation in the most common form of NPC disease in patients and disease progression which recapitulates the neuropathological and biochemical abnormalities observed in these patients. Using the feline model, we achieved highly encouraging results following intrathecal HPssCD administration in that clinical neurological signs of disease were completely resolved at least up to 24 weeks of age (an age when untreated cats die), however, we identified a completely unanticipated dose-related toxic effect on the auditory system. We will utilize our highly innovative feline model to further evaluate disease pathogenesis and the therapeutic efficacy of HPssCD via the following aims: Specific Aim 1. Determine whether the CSF concentration of HPssCD predicts amelioration of NPC-related neurological disease and produces ototoxicity. Specific Aim 2. Identify sensitive and predictive biomarkers of neurological disease to monitor disease progression and treatment efficacy and provide insight into pathogenesis. Specific Aim 3. Evaluate non-invasive nuclear magnetic resonance (NMR) measures of brain disease progression and treatment efficacy. PUBLIC HEALTH RELEVANCE: In order to ultimately develop efficacious and safe compounds for therapy of NPC disease, the pharmacology, mechanism of action, and toxicity of experimental drug therapy must be understood and is possible using this model system. The paucity of validated surrogate markers of brain disease which could be monitored as secondary clinical endpoints presents a major obstacle in clinical trials in NPC disease, and the studies proposed will validate both biochemical and imaging markers of disease severity and therapeutic outcome in the feline model of NPC disease using techniques which are applicable to affected children.