A Therapeutic DNA Epitope Vaccine for Alzheimer's Disease

阿尔茨海默病治疗性 DNA 表位疫苗

基本信息

批准号：
7888258
负责人：
CLAIRE Frances EVANS
金额：
$ 31.19万
依托单位：
ICHOR MEDICAL SYSTEMS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-08 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888258
关键词：
AN-1792 Achievement Acute Adjuvant Adverse effects Adverse event Advisory Committees Affect Alzheimer&apos s Disease Amyloid Animal Model Animals Antibodies Antibody Formation B-Lymphocyte Epitopes Behavioral Biodistribution Brain California Cell Death Cells Characteristics Chemistry Clinical Clinical Protocols Clinical Research Clinical Trials Clinical Trials Design Consensus Cyclic GMP DNA DNA Vaccines DNA delivery Data Dementia Deposition Detection Development Devices Diagnosis Disease Disease Progression Disease model Dose Elderly Electroporation Epitopes Etiology Evaluation Exhibits Feedback Generations HIV vaccine Healthcare Human Immune response Immunization Immunization Schedule Immunotherapy Impaired cognition In Vitro Injection of therapeutic agent Institutes Intervention Laboratories Light Macaca Mediating Medical Methods Molecular Medicine Monoclonal Antibodies Mus Pathology Patients Peptide Vaccines Peptides Performance Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Plasmids Positioning Attribute Primates Production Protocols documentation Rattus Recombinant DNA Research Design Research Ethics Committees Role Safety Schedule Secondary Immunization Serum Small Business Innovation Research Grant Staging System T cell response Technology Testing Tg2576 Therapeutic Time Tissues Toxic effect Toxicology Transgenic Mice Translations United States Universities Vaccinated Vaccines authority autoreactive T cell base cGMP production clinical research site cognitive function cohort design healthy volunteer immunogenicity manufacturing process manufacturing scale-up meetings mouse model neurofibrillary tangle formation neuroinflammation nonhuman primate novel novel strategies novel vaccines peptide A peptide based vaccine prevent programs prophylactic research clinical testing response theories therapy development time use vaccine candidate vaccine delivery

项目摘要

Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is estimated that there are currently more than 18 million people worldwide with AD and this number is projected to nearly double by 2025 to 34 million. The enormous, increasing worldwide healthcare burden of AD and the lack of effective drugs indicate new prophylactic and/or therapeutic approaches for treating AD are essential. One neuropathological feature of the disease is the presence of plaques composed primarily of a peptide called b- amyloid (A?). Currently, the predominant theory of the etiology of AD is that A? has a central role in the onset and progression of AD. According to this hypothesis, the accumulation of A? peptide, either by overproduction or aberrant clearance, results in the deposition of A? in plaques, which promotes the formation of neurofibrillary tangles and cell death, resulting in dementia. Many strategies for the development of therapies for AD are aimed at reducing the level of A? in the brain and/or blocking assembly of the peptide into pathological forms that disrupt cognitive function. A variety of approaches based on active (i.e., vaccines) or passive (i.e., monoclonal antibodies) immunotherapy against A? have demonstrated the capability to alter A? plaque burden in disease models and early phase clinical trials. The most advanced clinical trial evaluated an A? peptide vaccine (AN1792) developed by Elan Pharmaceuticals. Although a reduction in AD-related cognitive decline was observed in some of the immunized subjects, the trial was halted prematurely due to the occurrence of neuroinflammation in a subset of vaccine recipients. Subsequent analysis implicated the induction of autoreactive T cell responses to the A? peptide (but not antibody responses) in the development of these adverse events. Based on these findings, an A? B cell epitope DNA vaccine, ADepVac, was designed to elicit potent antibody responses to A? while avoiding the development of autoreactive T-cells. This candidate has demonstrated compelling safety and efficacy characteristics in AD murine disease models and strong synergy with electroporation-based DNA delivery technology. To evaluate the long term potential of this product as an intervention for AD, Ichor and its collaborators propose that the objective of SBIR U44 Phase I will be to verify that ADepVac can safely and effectively induce target levels of immune responses in non-human primates when delivered with electroporation-mediated delivery. If the safety and performance feasibility criteria are achieved, U44 Phase II will be initiated in order to complete the nonclinical safety/toxicological studies and regulatory filings necessary to support the initiation of a Phase I clinical trial in humans. Based on the diverse, interdisciplinary expertise assembled among the program collaborators, the project is well positioned to bring ADepVac into clinical testing.

阿尔茨海默病（AD）是老年人最常见的痴呆症。据估计，目前全球有超过 1800 万人患有 AD，预计到 2025 年这一数字将增加近一倍，达到 3400 万。 AD 带来的巨大且不断增加的全球医疗保健负担以及有效药物的缺乏表明治疗 AD 的新预防和/或治疗方法至关重要。该疾病的一个神经病理学特征是存在主要由称为 b-淀粉样蛋白 (A?) 的肽组成的斑块。目前，AD病因学的主流理论是A？在 AD 的发生和进展中起着核心作用。根据这个假设，A？肽，无论是过量生产还是异常清除，都会导致A？斑块中，促进神经原纤维缠结和细胞死亡的形成，导致痴呆。开发 AD 疗法的许多策略都是为了降低 A? 的水平。在大脑中和/或阻止肽组装成破坏认知功能的病理形式。基于针对 A 的主动（即疫苗）或被动（即单克隆抗体）免疫疗法的多种方法？已经证明有能力改变A？疾病模型和早期临床试验中的斑块负担。最先进的临床试验评估为 A？肽疫苗（AN1792）由Elan Pharmaceuticals 开发。尽管在一些免疫受试者中观察到与 AD 相关的认知能力下降有所减轻，但由于部分疫苗接种者出现神经炎症，该试验提前停止。随后的分析表明诱导了自身反应性T细胞对A？肽（但不是抗体反应）在这些不良事件的发展中。根据这些发现，A？ B 细胞表位 DNA 疫苗 ADepVac 旨在引发针对 A？同时避免自身反应性 T 细胞的发展。该候选药物在 AD 小鼠疾病模型中表现出引人注目的安全性和有效性特征，并与基于电穿孔的 DNA 递送技术具有强大的协同作用。为了评估该产品作为 AD 干预措施的长期潜力，Ichor 及其合作者提出，SBIR U44 第一阶段的目标是验证 ADepVac 在以下情况下能够安全有效地诱导非人类灵长类动物达到目标水平的免疫反应：通过电穿孔介导的递送来递送。如果达到安全性和性能可行性标准，U44 II 期将启动，以完成支持启动人体 I 期临床试验所需的非临床安全/毒理学研究和监管备案。基于项目合作者之间汇集的多元化、跨学科专业知识，该项目完全有能力将 ADepVac 引入临床测试。