Intrathecal cyclodextrin therapy of feline Niemann-Pick type C disease

描述（由申请人提供）：尼曼-皮克C型（NPC）病是一种进行性儿童神经系统疾病，以痴呆、共济失调和死亡为特征，通常发生在第一个或第二个十年。尽管已经发现了300多种致病突变，但迄今为止，成功治疗鼻咽癌的疗法仍是无效的。2-羟丙基-ss-环糊精（HPssCD）是fda指定的孤儿药（2010年5月），基于皮下治疗的npc1-/-小鼠和猫的良好治疗结果数据，目前正在用于少数患有NPC疾病的儿童。然而，由于患者样本量小，并且由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研究药物作用机制和潜在毒性。我们建议严格评估猫模型的药理学、机制和毒性问题，该模型具有NPC1 （2864G-C）自发发生的错感突变，该突变与患者中最常见的鼻咽癌疾病中最常见的突变同源，并且疾病进展概括了这些患者中观察到的神经病理和生化异常。使用猫模型，我们取得了非常令人鼓舞的结果，在鞘内给予HPssCD后，疾病的临床神经症状至少在24周龄（未经治疗的猫死亡的年龄）完全解决，然而，我们发现了完全出乎意料的剂量相关的听觉系统毒性作用。我们将利用我们高度创新的猫模型，通过以下目标进一步评估HPssCD的疾病发病机制和治疗效果：确定HPssCD的脑脊液浓度是否预测npc相关神经系统疾病的改善和产生耳毒性。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效果，并提供发病机制的见解。具体目标3。评估非侵入性核磁共振（NMR）测量脑疾病进展和治疗效果。

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.