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

• 批准号: 10524751
• 负责人: CHARLES H VITE
• 金额: $ 55.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10524751
• 关键词: Adverse effects; Affect; Animal Model; Ataxia; Basal Ganglia; Binding; 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; 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

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.

项目摘要/摘要 Niemann-Pick疾病C1（NPC1疾病）是一种遗传性疾病，其特征是溶酶体储存 胆固醇和鞘脂，以及进行性小脑共济失调，痴呆，垂直的临床体征 近视凝视麻痹，吞咽困难和早期死亡。 NPC1没有FDA批准的疗法 疾病。在2-羟基丙烷-beta-cyclodextrin（HPßCD）中重复施用Intracisterna magna（IC） 患有NPC1疾病的猫阻止了小脑共济失调的发作，防止了Purkinje细胞死亡，并将其归一化 小脑皮质和脑皮层胆固醇和神经节苷脂浓度，并增加了生存时间。 这些临床前数据将ICHPßCD提高到已证明效率的临床试验中。 但是，必须在患者的寿命期间每两周一次管理HPßCD，并导致 进行性限制剂量的耳毒性，强调了对这些侵入性和更安全疗法的明显需求 患者。 我们假设使用AAV9载体将NPC1传递到大脑的IC基因治疗优化 有效防止NPC1疾病相关的小脑共济失调和浦肯野病理病理 终身注射，没有耳毒性。我们还假设新颖的核内（IV）给药 猫的AAV血清型可以将NPC1传递到基底神经节和脑干，而该区域未经IC处理 hpßcd或aAV9的给药，并负责肌张力障碍，垂直上的凝视麻痹和 吞咽困难。因此，在拟议的研究中，我们将评估优化AAV9介导的方法 最大数量的Purkinje细胞的转导（AIM 1）评估AAV9-NPC1的效率 治疗NPC1相关小脑疾病的临床，生化和组织学方面的管理 2），并评估核内AAV-NPC1给药的效率 负责痴呆症（脑皮质），肌张力障碍（基底神经节）和垂直的上尖上凝视和 吞咽困难（脑干）（目标3）。 这些概念验证研究将是第一个优化不可扩散膜结合的递送的研究 purkinje细胞的蛋白质，从而推进许多其他影响Purkinje的遗传疾病的基因疗法 包括脊椎小脑共济失调在内的细胞。此外，这些研究将是第一个开发一次性疗法的研究 对于治疗小脑和脑外疾病的NPC1疾病，没有导致耳毒性。