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.

阿尔茨海默氏病（AD）是老年痴呆症最常见的形式。据估计，目前，全球有超过1800万人的广告，预计到2025年，这一数字将几乎翻一番，达到3400万。 AD的全球医疗保健负担增加，缺乏有效的药物表明治疗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病因的主要理论是A？在AD的发作和进展中起着核心作用。根据这一假设，A的积累？肽是由于过量生产还是异常清除率，导致A的沉积？在斑块中促进了神经原纤维缠结和细胞死亡的形成，导致痴呆。开发AD疗法的许多策略旨在降低A的水平？在大脑和/或阻断肽的组装中，将破坏认知功能的病理形式。基于主动（即疫苗）或被动（即单克隆抗体）免疫疗法的各种方法？已经证明了改变A的能力？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了A？由Elan Pharmaceuticals开发的肽疫苗（AN1792）。尽管在某些免疫受试者中观察到与AD相关的认知下降的降低，但由于疫苗接收者子集中神经炎症的发生，试验过早停止了试验。随后的分析暗示自动反应性T细胞对A的响应？在这些不良事件的发展中，肽（但不是抗体反应）。根据这些发现，A？ B细胞表位DNA疫苗EDEPVAC旨在引起对A的有效抗体反应？同时避免自动反应性T细胞的发展。该候选人在AD鼠类疾病模型中表现出了令人信服的安全性和功效特征，并且与基于电穿孔的DNA递送技术有着强大的协同作用。为了评估该产品作为AD的长期潜力，Ichor及其合作者提出SBIR U44阶段I的目的是验证ADEPVAC在用电穿孔介导的介导的交付时，ADEPVAC可以安全有效地诱导非人类灵长类动物的免疫反应的目标水平。如果达到安全性和性能可行性标准，将启动U44阶段，以完成支持人类I期临床试验所需的非临床安全/毒理学研究和调节申请。基于计划合作者之间组成的多样化的跨学科专业知识，该项目有效地将EDEPVAC带入临床测试。