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

 描述(申请人提供)：阿尔茨海默病(AD)的临床特征是进行性认知能力下降，最终导致死亡，通常在确诊后10年内。据估计，全球痴呆症患者的数量为3560万人，相信到2050年这一数字将达到1亿。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。建议的U01项目的主要目标是将我们团队开发的药用级DNA表位候选疫苗(AV-1959D)转化为临床。最近，我们的团队报道了这种新型的基于DNA的AD表位疫苗的研制，该疫苗由一个短小的免疫原性B细胞淀粉样蛋白表位(3个拷贝：3A MHC 1-11)与多种已知可被各种人类免疫反应基因识别的通用外源Th表位(称为βII类)的平台融合而成。通过电穿孔系统提供的AV-1959D疫苗对外来表位产生强大的细胞免疫反应，消除潜在有害的自身反应性T细胞的激活，并在小鼠、兔子和猴子中诱导强大的、具有治疗效力的抗Aβ抗体(已发表4篇论文)。在细胞免疫应答方面，AV-1959D降低了猕猴MHC-II类免疫应答的变异性，并在所有免疫动物中激活了针对多TEP平台表位的Th细胞。因此，在2009-2012年由NINDS资助的我们的U44项目框架内，我们生产了我们的领先候选DNA疫苗AV-1959D，并于2012年12月完成了与FDA的IND前会议。在这个U01项目中，我们建议使用为小鼠研究而改装的AgilePulseTM体内电穿孔系统完成APP/TG小鼠(3xTg-AD)的临床前疗效、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小鼠身上进行，这些小鼠具有不同阶段的AD样病理。此外，将在患有广泛CAA的TG-SwD/I小鼠身上进行一项安全性研究，评估疫苗对神经病理(如脑膜相关炎症、微出血、血管变性、血管源性水肿等)的影响。在这些研究完成后，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、毒物学家和临床药物开发商 而在AD早期和晚期临床试验方面拥有丰富经验的研究人员将获得 所有必要的法规文件和FDA批准的用于AV-1959D第一阶段试验的IND。

 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.