Pre-clinical study to fulfill FDA requirements for the completion of AV-1959 IND

临床前研究以满足 FDA 完成 AV-1959 IND 的要求

• 批准号: 8887223
• 负责人: Michael G Agadjanyan
• 金额: $ 115.22万
• 依托单位: INSTITUTE FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887223
• 关键词: Advisory Committees; Affect; Althaea; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Amyloid beta-Protein; Animals; Antibodies; B-Lymphocyte Epitopes; Biodistribution; Biological; Biotechnology; Blood Vessels; Brain; Businesses; Cells; Cessation of life; Clinic; Clinical; Clinical Protocols; Clinical Trials; Cognitive; Cyclic GMP; DNA; DNA Vaccines; Deposition; Development; Diagnosis; Dose; Drug Evaluation; Edema; Electroporation; Epitopes; Evaluation; FDA approved; Funding; Future; Generations; Goals; Histocompatibility Antigens Class II; Human; Immune Response Genes; Immune response; Immunologist; Impaired cognition; Individual; Infiltration; Inflammation; Institutes; Investigational Drugs; Investigational New Drug Application; Life; Lymphocyte; MHC Class II Genes; Macaca; Medical; Meningeal; Molecular; Molecular Medicine; Monkeys; Mus; National Institute of Neurological Disorders and Stroke; Necrosis; New Drug Approvals; Oryctolagus cuniculus; Paper; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Plasmids; Publishing; Recombinant DNA; Recommendation; Reporting; Research Personnel; Safety; Scientist; Staging; System; Technology; Toxicology; Transgenic Mice; Translations; United States; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; autoreactive T cell; base; clinical efficacy; cost; experience; extracellular; immunogenic; in vivo; meetings; mouse model; multidisciplinary; neuropathology; novel; phase 1 study; phase I trial; pre-clinical; preclinical efficacy; preclinical study; programs; public health relevance; research study; response; safety study; vaccine candidate

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized clinically by progressive cognitive decline, eventually resulting in death, usually within 10 years of the diagnosis. The number of demented individuals worldwide is estimated to be 35.6 million people, and it is believed that it will reach 100 million by the year 2050. According to the Alzheimer's Association, in 2013, AD will cost the United States $203 billion. This number is expected to rise to $1.2 trillion by 2050. The main goal of the proposed U01 project is a translation to the clinic of the pharmaceutical-grade DNA epitope vaccine candidate (AV-1959D) developed by our team. Recently, our team reported on generating this novel, DNA-based AD epitope vaccine composed of a short immunogenic B cell epitope of amyloid (3 copies: 3Aβ1-11), fused with a platform of multiple universal foreign Th epitopes (designated as MultiTEP) that are known to be recognized by various human immune response genes (MHC class II). Delivered by an electroporation system, the AV-1959D vaccine generates robust cellular immune responses to foreign epitopes, eliminates activation of potentially harmful autoreactive T cells and induces strong and therapeutically potent anti-Aβ antibodies in mice, rabbits, and monkeys (4 papers published). As to the cellular immune responses, AV-1959D diminished the variability of immune responses due to MHC Class II diversity, in macaques, and activated Th cells specific to epitopes from MultiTEP platform in all vaccinated animals. Accordingly, in the frame of our U44 program funded by NINDS in 2009-2012 we manufactured our leading candidate DNA vaccine, AV-1959D and completed a pre-IND meeting with the FDA in Dec of 2012. In this U01 project we propose completing the pre-clinical efficacy, safety/toxicology and biodistribution studies in APP/Tg mice (3xTg-AD) using an AgilePulseTM in vivo Electroporation system modified for mouse studies. These studies, according to FDA recommendations will be performed in two groups of 3xTg-AD mice, possessing different stages of AD-like pathology. Additionally, a safety study evaluating the affect of the vaccine on neuropathology (such as meningeal-related inflammation, microhemorrhage, vascular degeneration, vasogenic edema, etc) will be performed in Tg-SwD/I mice with extensive CAA. At the completion of these studies our multidisciplinary team, including immunologists, vaccine researchers, neuroscientists/cognitive scientists, molecular biologists, toxicologists, clinical drug developers and investigators with extensive experience in AD early and late phase clinical trials, will obtain all of the necessary regulatory documents and an FDA- approved IND for AV-1959D Phase I trials.

 描述（由申请人提供）：阿尔茨海默病（AD）的临床特征是进行性认知下降，最终导致死亡，通常在诊断后10年内。据估计，全世界痴呆症患者人数为3560万人，据信到2050年将达到1亿人。根据阿尔茨海默氏症协会的数据，2013年，AD将花费美国2030亿美元。预计到2050年，这一数字将上升到1.2万亿美元。U 01项目的主要目标是将我们团队开发的药物级DNA表位候选疫苗（AV-1959 D）转化为临床。最近，我们的团队报道了产生这种新型的基于DNA的AD表位疫苗，其由淀粉样蛋白的短免疫原性B细胞表位（3个拷贝：3Aβ1-11）与已知被各种人类免疫应答基因（MHC II类）识别的多个通用外源Th表位（命名为MultiTEP）的平台融合组成。AV-1959 D疫苗通过电穿孔系统递送，可对外源表位产生强大的细胞免疫应答，消除潜在有害的自身反应性T细胞的激活，并在小鼠、兔和猴中诱导强效和治疗有效的抗A β抗体（已发表4篇论文）。至于细胞免疫应答，AV-1959 D在猕猴中减少了由于MHC II类多样性引起的免疫应答的可变性，并在所有接种疫苗的动物中激活了对来自MultiTEP平台的表位具有特异性的Th细胞。因此，在2009-2012年由NINDS资助的U44项目框架内，我们生产了我们领先的候选DNA疫苗AV-1959 D，并于2012年12月与FDA完成了IND前会议。在本U 01项目中，我们建议使用针对小鼠研究改良的AgilePulseTM体内电穿孔系统，在APP/Tg小鼠（3xTg-AD）中完成临床前疗效、安全性/毒理学和生物分布研究。根据FDA的建议，这些研究将在两组3xTg-AD小鼠中进行，这些小鼠具有不同阶段的AD样病理学。此外，将在患有广泛CAA的Tg-SwD/I小鼠中进行一项安全性研究，评价疫苗对神经病理学（如脑膜相关炎症、微出血、血管变性、血管源性水肿等）的影响。在完成这些研究时，我们的多学科团队，包括免疫学家，疫苗研究人员，神经科学家/认知科学家，分子生物学家，毒理学家，临床药物开发人员 以及在AD早期和晚期临床试验中具有丰富经验的研究者，将获得 所有必要的监管文件和FDA批准的AV-1959 D I期试验的IND。