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: 10404485
• 负责人: Beverly L. Davidson
• 金额: $ 180.24万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404485
• 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（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，并伴有大脑皮层多个区域的神经元死亡。目前的治疗方法都是针对症状的，并且没有可用的治疗方法可以改变疾病的自然史。在之前的概念验证研究中，在强大的人类遗传学数据的支持下，我们证明，将腺相关病毒 (AAV) 载体单次注射到 AD 小鼠的侧脑室中，可导致室管膜细胞持续表达 APOE2 并分泌进入脑脊液（CSF）。一旦进入脑脊液，这种蛋白质就会分布到整个大脑，对许多 AD 相关表型产生有益的影响。此外，在非人类灵长类动物中也使用相同的方法实现了治疗表达水平。在这里，我们建议通过一个里程碑驱动的过程来推动我们的治疗载体，最终以人类受试者 1 期临床试验的 IND 申请结束。具体来说，我们建议 1) 与 FDA 的 CBER 举行 IND 前 B 类会议，以接收有关计划中的 GLP 毒理学研究和拟议的 1 期方案设计的意见； 2) 产生GMP工艺可比载体（GLP载体）； 3) 在非人类灵长类动物（恒河猴）中进行支持 IND 的 GLP 药物/毒性研究； 4) 生成GMP级载体； 5) 准备并向 FDA 提交 IND，用于早期症状性 AD 受试者的 I/II 期临床试验。