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：
8447003
负责人：
CHARLES H VITE
金额：
$ 33.78万
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/8447003
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）：Niemann-Pick型C（NPC）疾病是一种痴呆症，共济失调和死亡的儿童的进行性神经系统疾病，通常在第一或第二个十年内。尽管确定了300多个病因突变，但成功治疗NPC疾病的疗法至今仍无效。 2- FDA指定的孤儿药物（2010年5月），羟丙基SS-Cyclodextrin（HPSSCD）（HPSSCD）正在对少数NPC疾病的儿童进行施用，该儿童基于皮下处理的NPC1-/ - 小鼠和猫的有利治疗结果数据。但是，由于患者的样本量较小，并且由于道德原因而无法对正常儿童进行控制研究，因此人类患者无法解决药物作用和潜在毒性的机制。 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.使用猫科动物模型，我们在鞘内HPSSCD给药后取得了极大的令人鼓舞的结果，因为临床神经系统疾病的迹象至少至少在24周龄（未经处理的猫死亡的年龄）完全解决了，但是，我们确定了一种完全意外的意外剂量相关的毒性对听觉系统。我们将利用高度创新的猫科动物模型通过以下目的进一步评估HPSSCD的疾病发病机理和治疗功效：具体目的1。确定HPSSCD的CSF浓度是否可以预测NPC相关神经疾病的改善，并产生静脉毒性。具体目的2。确定神经疾病的敏感和预测性生物标志物，以监测疾病的进展和治疗功效，并提供对发病机理的见解。具体目的3。评估脑疾病进展和治疗功效的非侵入性核磁共振（NMR）测量。