Therapeutic APOE2 overexpression for early Alzheimer's disease

APOE2 过表达治疗早期阿尔茨海默病

• 批准号: 9922393
• 负责人: Beverly L. Davidson
• 金额: $ 132.15万
• 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/9922393
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Apolipoprotein E; Appearance; Area; Back; Biological; Brain; Cell secretion; Cerebral cortex; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Clinical; Clinical Trials; Cognition; Data; Disease; Disease model; Dose; E protein; Ependymal Cell; Epidemic; Family; Future; Genes; Healthcare; Homozygote; Human; Human Genetics; Impaired cognition; In Vitro; Injections; Macaca mulatta; Medicine; Mus; Neurodegenerative Disorders; Pathologic; Patients; Pediatric Hospitals; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Phenotype; Philadelphia; Process; Production; Protein Isoforms; Protocols documentation; Risk; Route; Safety; Series; Societies; Therapeutic; Toxicology; Variant; Viral; Work; adeno-associated viral vector; design; disease natural history; gene therapy; genetic risk factor; human subject; in vivo; lateral ventricle; meetings; mouse model; neuron loss; nonhuman primate; overexpression; pre-clinical; programs; protective allele; protein distribution; rare variant; 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（Alzheimer's disease，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，伴有大脑皮层多个区域的神经元死亡。目前的治疗是对症的，没有可用的治疗方法可以改变疾病的自然史。在先前的概念验证研究中，并得到了强有力的人类遗传学数据的支持，我们证明了腺相关病毒（AAV）载体单次注射到AD小鼠的侧脑室中导致室管膜细胞持续表达APOE 2并分泌到脑脊液（CSF）中。一旦进入CSF，这种蛋白质分布在整个大脑中，对许多AD相关表型具有有益作用。此外，在非人灵长类动物中使用相同的方法也实现了治疗水平的表达。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，该过程以在人类受试者中进行1期临床试验的IND申请结束。具体而言，我们建议：1）与FDA CBER举行一次B类IND前会议，以接收关于计划GLP毒性研究设计和拟定I期方案的输入; 2）生产GMP工艺可比载体（GLP载体）; 3）在非人灵长类动物中进行IND使能GLP药物/毒性研究（恒河猴）; 4）产生GMP级载体;和5）制备IND并向FDA提交，用于在患有早期症状性AD的受试者中进行I/II期临床试验。