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)病是一种进行性的儿童神经系统疾病，其特征是痴呆、共济失调和死亡，通常在第一或第二个十年内。尽管发现了300多种致病突变，但成功治疗鼻咽癌疾病的疗法迄今尚未奏效。2-羟丙基-SS-环糊精(HPssCD)是FDA指定的孤儿药物(2010年5月)，目前正用于少数鼻咽癌儿童，根据皮下治疗NPC1-/-猫和NPC1-/-小鼠和猫的良好治疗结果数据。然而，由于患者样本量小，以及由于伦理原因无法在正常儿童中进行对照研究，药物作用机制和潜在毒性在人类患者中无法解决。我们建议严格评估猫科动物模型中的药理学、机制和毒性问题，该模型在NPC1(2864G-C)中存在自发发生的错义突变，与患者最常见的鼻咽癌疾病中最常见的突变以及疾病进展(概括了在这些患者中观察到的神经病理和生化异常)同源。在猫的模型中，我们在鞘内注射HPssCD后取得了非常令人鼓舞的结果，因为临床神经系统疾病的体征至少在24周龄(未治疗的猫死亡的年龄)前就完全消失了，然而，我们发现了对听觉系统完全意想不到的剂量相关毒性影响。我们将利用我们高度创新的猫科动物模型，通过以下目标进一步评估疾病发病机制和HPssCD的治疗效果：特定目标1.确定HPssCD的脑脊液浓度是否预测鼻咽癌相关神经疾病的改善和产生耳毒性。明确目标2.确定神经系统疾病的敏感和预测生物标记物，以监测疾病进展和治疗效果，并提供对发病机制的洞察。具体目的3.评价脑部疾病进展和治疗效果的非侵入性核磁共振测量方法。

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.