Intrathecal cyclodextrin therapy of feline Niemann-Pick type C disease

鞘内环糊精治疗猫 C 型尼曼匹克病

基本信息

批准号：
8629803
负责人：
CHARLES H VITE
金额：
$ 34.65万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8629803
关键词：
Action Potentials Address Adolescent Affect Age Ataxia Auditory system Biochemical Biochemical Markers Biological Markers Biological Models Blood - brain barrier anatomy Brain Diseases Brain Pathology Central Nervous System Diseases Cessation of life Child Cholesterol Cholesterol Homeostasis Clinical Clinical Trials Controlled Study Cyclodextrins Data Dementia Disease Disease Progression Dose Drug Kinetics Drug effect disorder Ethics Evaluation Family Felidae Felis catus Gliosis Hearing Heterogeneity Human Image Liver diseases Longitudinal Studies Lung diseases Measures Methods Missense Mutation Modeling Monitor Mus Mutation N-acetylaspartate Neurologic Neurons Nuclear Magnetic Resonance Orphan Drugs Outcome Pathogenesis Pathology Patients Pharmacology Pharmacotherapy Plasma Proteins Regulation Sample Size Severity of illness Sphingosine Subarachnoid Space Supraoptic Vertical Ophthalmoplegia Surrogate Markers Swelling Techniques Testing Therapeutic Toxic effect Treatment Efficacy Treatment outcome Tryptophan base calbindin disease-causing mutation in vivo innovation insight nervous system disorder neuron loss neurotoxic ototoxicity public health relevance remediation

项目摘要

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.

描述（由申请人提供）：尼曼-皮克 C 型（NPC）疾病是一种进行性儿童神经系统疾病，其特征是痴呆、共济失调，通常在第一个或第二个十年内死亡。尽管已鉴定出 300 多种致病突变，但迄今为止成功治疗鼻咽癌的疗法仍无效。 2-羟丙基-ss-环糊精 (HPssCD) 是 FDA 指定的孤儿药（2010 年 5 月），根据皮下治疗的 npc1-/- 小鼠和猫。然而，由于患者样本量较小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研究药物作用机制和潜在毒性。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，该猫模型在 NPC1 (2864G-C) 中具有自发发生的错义突变，该突变与患者和疾病中最常见的 NPC 疾病形式中最常见的突变同源。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。使用猫科动物模型，我们在鞘内 HPssCD 给药后取得了非常令人鼓舞的结果，疾病的临床神经系统症状至少在 24 周龄（未经治疗的猫死亡的年龄）内得到完全解决，然而，我们发现了完全意想不到的剂量 -对听觉系统的相关毒性作用。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：具体目标 1. 确定 HPssCD 的 CSF 浓度是否预测鼻咽癌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效果，并深入了解发病机制。具体目标 3. 评估脑部疾病进展和治疗效果的非侵入性核磁共振 (NMR) 测量。