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，其特征在于： 逐渐出现进行性认知功能障碍伴多个区域神经元死亡 大脑皮层的一部分。目前的治疗是对症的，没有可用的治疗方法 改变疾病的自然病程在以前的概念验证研究中， 强有力的人类遗传学数据，我们证明，单次注射腺相关病毒， 病毒（AAV）载体进入AD小鼠的侧脑室导致持续的APOE 2表达 从室管膜细胞分泌到脑脊液中。一旦进入脑脊液， 蛋白质分布在整个大脑中，对许多AD相关的 表型此外，使用相同的方法也实现了治疗水平的表达。 在非人类灵长类动物中的方法。 在这里，我们建议通过一个里程碑驱动的过程， 在人类受试者中进行1期临床试验的IND申请。具体而言，我们建议 1)与FDA的CBER举行一次IND前B类会议，以接收关于设计的输入 计划的GLP毒性研究和拟定的I期方案; 2）生产GMP工艺 可比载体（GLP载体）; 3）在非人中进行IND使能GLP药物/毒性研究 灵长类动物（恒河猴）; 4）生成GMP级载体;以及5）制备并归档IND 在早期症状性AD受试者中进行I/II期临床试验。