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.

阿尔茨海默氏病（AD）是最常见的神经退行性疾病，其特征是在大脑皮质多个区域逐渐出现逐渐出现与神经元死亡的进行性认知功能障碍。当前的疗法是有症状的，没有可改变疾病自然病史的可用疗法。在先前的概念验证研究中，并获得了强大的人类遗传学数据的支持，我们证明了将腺相关病毒（AAV）向量单次注射到AD小鼠外侧心室中，导致ape2持续的APOE2从de频细胞中持续表达，并分泌到大脑脊髓液（CSF）中。进入CSF后，该蛋白质会在整个大脑中分布，对许多与AD相关的表型产生有益的作用。此外，在非人类灵长类动物中使用相同的方法，还可以实现治疗水平的表达水平。在这里，我们建议将治疗载体通过里程碑驱动的过程移动，该过程以IND申请在人类受试者中进行1期临床试验。具体而言，我们建议1）与FDA的CBER举行预先印度的B型会议，以接收有关计划的GLP TOX研究设计和拟议的1阶段协议的意见； 2）产生GMP过程可比载体（GLP载体）； 3）在非人类灵长类动物（Rhesus Macaques）中执行GLP Pharm/TOX研究； 4）生成GMP级向量； 5）在患有早期症状AD的受试者中，为I/II期临床试验准备IND并向IND提交IND。