AAV-mediated gene therapy for CNS disease correction in feline NPC1 disease

AAV 介导的基因治疗可纠正猫科动物 NPC1 疾病的中枢神经系统疾病

基本信息

批准号：
10643054
负责人：
CHARLES H VITE
金额：
$ 5.69万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643054
关键词：
Adverse effects Affect Animal Model Ataxia Basal Ganglia Binding Proteins Biochemical Brain Brain Diseases Brain Stem Cell Death Cell Survival Central Nervous System Diseases Cerebellar Ataxia Cerebellar Diseases Cerebellum Cerebral cortex Cessation of life Cholesterol Clinic Clinical Clinical Trials Collaborations Combined Modality Therapy Complementary DNA Data Deglutition Disorders Dementia Disease Dose-Limiting Dystonia Engineering Evaluation FDA approved Family Felidae Felis catus Gangliosides Genetic Diseases Hereditary Disease Histologic Injections Intracarotid Life Mediating Membrane Methods Modeling Mus NPC1 gene Niemann-Pick Diseases Other Genetics Pathology Patients Proteins Purkinje Cells Reporter Genes Reproducibility Research Personnel Route Safety Serotyping Sphingolipids Spinocerebellar Ataxias Testing Time Transgenes Translating Viral Vector adeno-associated viral vector base brain size causal variant cisterna magna efficacy clinical trial efficacy evaluation gaze palsy gene therapy hydroxypropyl-beta-cyclodextrin nonhuman primate novel ototoxicity pre-clinical prevent protein expression vector

项目摘要

Project Summary/Abstract Niemann-Pick disease type C1 (NPC1 disease) is a hereditary disorder characterized by the lysosomal storage of cholesterol and sphingolipids, and clinical signs of progressive cerebellar ataxia, dementia, vertical supranuclear gaze palsy, dysphagia, and early death. There are no FDA-approved therapies for NPC1 disease. Repeated intracisterna magna (IC) administration of 2-hydroxypropyl-beta-cyclodextrin (HPßCD) in cats with NPC1 disease prevented the onset of cerebellar ataxia, prevented Purkinje cell death, normalized cerebellocortical and cerebrocortical cholesterol and gangliosides concentrations, and increased survival time. These preclinical data advanced IC HPßCD into clinical trials where efficacy has been demonstrated. However, HPßCD must be administered IC every two weeks for the duration of the patient’s life and results in progressive dose-limiting ototoxicity, highlighting a clear need for less invasive and safer therapies for these patients. We hypothesize that optimization of IC gene therapy using an AAV9 vector to deliver NPC1 to the brain will effectively prevent NPC1 disease-associated cerebellar ataxia and Purkinje cell pathology without repeated lifelong injections and without ototoxicity. We also hypothesize that intracarotid (IV) administration of a novel AAV serotype to cats can deliver NPC1 to the basal ganglia and brainstem, regions which are untreated by IC administration of HPßCD or AAV9, and are responsible for dystonia, vertical supranuclear gaze palsy, and dysphagia. Therefore, in the proposed studies we will assess methods to optimize AAV9-mediated transduction of the greatest number of Purkinje cells (Aim 1), evaluate the efficacy of AAV9-NPC1 administration to treat clinical, biochemical, and histologic aspects of NPC1-associated cerebellar disease (Aim 2), and evaluate the efficacy of intracarotid AAV-NPC1 administration to treat extracerebellar regions responsible for dementia (cerebral cortex), dystonia (basal ganglia), and vertical supranuclear gaze palsy and dysphagia (brainstem) (Aim 3). These proof-of-concept studies will be the first to optimize the delivery of a non-diffusible membrane-bound protein to Purkinje cells, thereby advancing gene therapy for many other genetic diseases affecting Purkinje cells including spinocerebellar ataxias. Moreover, these studies will be the first to develop a one-time therapy for NPC1 disease that treats both cerebellar and extracerebellar disease and results in no ototoxicity.

项目概要/摘要 C1 型尼曼-匹克病（NPC1 病）是一种以溶酶体贮积为特征的遗传性疾病胆固醇和鞘脂的含量，以及进行性小脑共济失调、痴呆、垂直核上性凝视麻痹、吞咽困难和早期死亡目前尚无 FDA 批准的针对 NPC1 的治疗方法。在小脑池内 (IC) 重复施用 2-羟丙基-β-环糊精 (HPßCD)。患有 NPC1 疾病的猫可以预防小脑共济失调的发生，预防浦肯野细胞死亡，使其正常化脑皮质和脑皮质胆固醇和神经节苷脂浓度，并增加生存时间。这些临床前数据将 IC HPßCD 推进到临床试验中，并已证明其功效。然而，HPßCD 必须在患者一生中每两周进行一次 IC 给药，并导致渐进性剂量限制性耳毒性，突出表明明确需要针对这些疾病的侵入性更小且更安全的治疗方法患者。我们追求使用 AAV9 载体将 NPC1 递送至大脑的 IC 基因治疗的优化有效预防NPC1疾病相关的小脑共济失调和浦肯野细胞病理，无需重复我们还研究了一种新型的颈动脉内（IV）注射方法。猫的 AAV 血清型可以将 NPC1 递送至未接受 IC 治疗的基底神经节和脑干区域 HPßCD 或 AAV9 的管理，并负责肌张力障碍、垂直核上性凝视麻痹和因此，在拟议的研究中，我们将评估优化 AAV9 介导的方法。转导最大数量的浦肯野细胞（目标 1），评估 AAV9-NPC1 的功效给药治疗 NPC1 相关小脑疾病的临床、生化和组织学方面（目标 2），评估颈动脉内AAV-NPC1给药治疗小脑外区域的疗效导致痴呆（大脑皮层）、肌张力障碍（基底神经节）和垂直核上性凝视麻痹吞咽困难（脑干）（目标 3）。这些概念验证研究将是第一个优化非扩散膜结合的递送的研究浦肯野细胞蛋白，从而推进针对影响浦肯野细胞的许多其他遗传疾病的基因治疗此外，这些研究将是第一个开发一次性疗法的研究。用于治疗 NPC1 疾病，可治疗小脑和小脑外疾病，且不会产生耳毒性。