Supplemental Request: Therapeutic APOE2 overexpression for early Alzheimer's disease

补充请求：APOE2 过表达治疗早期阿尔茨海默病

• 批准号: 10596304
• 负责人: Beverly L. Davidson
• 金额: $ 139.34万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596304
• 关键词: Affect; Alzheimer' s Disease; Appearance; Area; Back; Brain; Cell secretion; Cerebral cortex; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Cognition; Data; Disease; Disease model; Ependymal Cell; Human Genetics; Impaired cognition; Injections; Macaca mulatta; Mus; Neurodegenerative Disorders; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Phenotype; Process; Protocols documentation; Safety; Therapeutic; Toxicology; Work; adeno-associated viral vector; design; disease natural history; human subject; lateral ventricle; meetings; mouse model; neuron loss; nonhuman primate; overexpression; vector

Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by the gradual appearance of progressive cognitive dysfunction with neuronal death in multiple areas of the cerebral cortex. Current therapies are symptomatic and there are no available treatments that alter the natural history of the disease. In previous proof-of-concept studies, and backed by strong human genetics data, we demonstrated that a single injection of an adeno-associated viral (AAV) vector into the lateral ventricle of AD mice leads to sustained APOE2 expression from ependymal cells and secretion into the cerebrospinal fluid (CSF). Once in the CSF, this protein distributes throughout the entire brain with a beneficial effect on many AD-related phenotypes. Moreover, therapeutic levels of expression were also achieved using the same approach in non-human primates. Here, we propose to move our therapeutic vector through a milestone-driven process that ends with an IND application for a Phase 1 clinical trial in human subjects. Specifically, we propose to 1) hold a Pre-IND Type B meeting with the CBER of the FDA to receive input on the design of the planned GLP tox study and the proposed Phase 1 protocol; 2) produce GMP-process comparable vector (GLP vector); 3) perform IND-enabling GLP pharm/tox studies in nonhuman primates (Rhesus macaques); 4) generate GMP-grade vector; and 5) prepare and file the IND with the FDA for a phase I/II clinical trial in subjects with early symptomatic AD.

阿尔茨海默病（AD）是最常见的神经退行性疾病，其特征是 逐渐出现进行性认知功能障碍并伴有多个区域的神经元死亡 大脑皮层的。目前的治疗方法都是针对症状的，没有可用的治疗方法 改变疾病的自然史。在之前的概念验证研究中，并得到了支持 强大的人类遗传学数据，我们证明单次注射腺相关 病毒（AAV）载体进入 AD 小鼠侧脑室导致 APOE2 持续表达 从室管膜细胞分泌到脑脊液（CSF）中。一旦进入脑脊液，这 蛋白质分布在整个大脑中，对许多与 AD 相关的疾病有有益作用 表型。此外，使用相同的方法也达到了治疗水平的表达 非人类灵长类动物的方法。 在这里，我们建议通过一个里程碑驱动的过程来移动我们的治疗载体，该过程结束 并提交 IND 申请，进行人类受试者的 1 期临床试验。具体来说，我们建议 1) 与 FDA 的 CBER 举行预 IND 类型 B 会议，以接收有关设计的意见 计划中的 GLP 毒性研究和拟议的第一阶段协议； 2) 生产GMP流程 可比向量（GLP向量）； 3) 在非人类中进行支持 IND 的 GLP 药物/毒性研究 灵长类动物（恒河猴）； 4) 生成GMP级载体； 5) 准备并提交 IND 与 FDA 合作，对患有早期症状 AD 的受试者进行 I/II 期临床试验。