Therapeutic APOE2 overexpression for early Alzheimer's disease

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。目前的治疗方法是对症治疗，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，并有强大的人类遗传学数据支持，我们证明了将腺相关病毒（AAV）载体单次注射到AD小鼠的侧脑室可导致室管膜细胞持续表达APOE2并分泌到脑脊液（CSF）中。一旦进入脑脊液，这种蛋白分布在整个大脑中，对许多ad相关的表型有有益的影响。此外，在非人类灵长类动物中，使用相同的方法也实现了治疗水平的表达。在这里，我们建议将我们的治疗载体通过一个里程碑驱动的过程，以在人类受试者中进行i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型会议，以接收关于计划GLP tox研究和拟议的1期方案设计的输入；2)生成gmp过程可比向量（GLP向量）；3)在非人类灵长类动物（恒河猴）中进行使能GLP的药物/毒素研究；4)生成gmp级矢量；5)准备并向FDA提交IND，用于早期症状性AD患者的I/II期临床试验。

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.