Anti tau scFvs - new tools to better understand and treat Alzheimer's disease

抗 tau 单链抗体 - 更好地了解和治疗阿尔茨海默病的新工具

• 批准号: 288227629
• 负责人: Dr. Christina Ising
• 金额: --
• 依托单位: Department of Neurology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/288227629?language=en
• 关键词: Anti; tau; scFvs; new; tools

Alzheimer's disease is the most common form of dementia, affecting about 35 million people worldwide with an increasing prevalence in our ageing society. The progression of Alzheimer's disease is associated with accumulation of amyloid-beta (Abeta) in amyloid plaques and tau in neurofibrillary tangles. Since Abeta aggregation precedes tau pathology, treatment strategies in the past years have focused on reducing amyloid plaque burden by active and passive immunization targeting Abeta. Although promising results have been achieved in mouse models of Alzheimer's disease (AD) this approach has not yet proven to be effective in clinical trials. Recent evidence suggests that accumulation of tau but not Abeta correlates with clinical symptoms in patients and that tau pathology spreads from cell-to-cell by a so far unknown mechanism. Dr. Holtzman's lab has previously shown that passive immunization with the in house made anti-tau antibody HJ8.5 decreased overall tau accumulation and slowed progression of the disease in a human tau P301S expressing transgenic mouse model of tauopathy. However, treatment of neurological diseases with antibodies remains difficult as a therapeutic strategy in humans due to only a small percentage of antibodies in the plasma being able to cross the blood-brain-barrier. Therefore, my project will focus on improving the feasibility of a treatment of AD and other tau related diseases with the HJ8.5 antibody utilizing a gene therapy approach targeting the central nervous system (CNS). To achieve this, single-chain fragment variable (scFv) antibodies, which consist of the variable region of the heavy and the light chain, connected by different peptide linkers, will be engineered and tested extensively in vitro and in vivo. scFvs have been shown to retain antigen-binding specificity and due to their small size yield good tissue penetration and can be easily packed into an adeno associated virus (AAV) for therapeutic delivery in the CNS. In addition to serving as a potential therapeutic agent, the scFvs will also be used as a biological tool to further elucidate the role of extracellular tau in tau propagation from cell to cell in vivo.

阿尔茨海默病是最常见的痴呆症，影响全球约3500万人，在我们老龄化的社会中发病率越来越高。阿尔茨海默病的进展与淀粉样蛋白斑块中淀粉样蛋白-β（Abeta）和神经元缠结中tau蛋白的积累相关。由于Abeta聚集先于tau病理，过去几年的治疗策略集中在通过靶向Abeta的主动和被动免疫来减少淀粉样蛋白斑块负荷。虽然在阿尔茨海默病（AD）小鼠模型中已经取得了有希望的结果，但这种方法尚未在临床试验中证明是有效的。最近的证据表明，tau蛋白而非Abeta蛋白的积累与患者的临床症状相关，并且tau蛋白病理学通过迄今未知的机制从细胞传播到细胞。Holtzman博士的实验室先前已经表明，在表达tau蛋白病的人tau P301 S转基因小鼠模型中，用自制的抗tau抗体HJ8.5被动免疫减少了总体tau蛋白积累并减缓了疾病的进展。然而，由于血浆中只有一小部分抗体能够穿过血脑屏障，因此用抗体治疗神经系统疾病作为人类的治疗策略仍然很困难。因此，我的项目将专注于提高利用靶向中枢神经系统（CNS）的基因治疗方法用HJ8.5抗体治疗AD和其他tau相关疾病的可行性。为了实现这一点，单链可变片段（scFv）抗体（其由通过不同肽接头连接的重链和轻链的可变区组成）将被工程化并在体外和体内进行广泛测试。已经显示scFv保留抗原结合特异性，并且由于它们的小尺寸而产生良好的组织渗透，并且可以容易地包装到腺相关病毒（AAV）中用于CNS中的治疗性递送。除了用作潜在的治疗剂之外，scFv还将用作生物学工具以进一步阐明细胞外tau在体内从细胞到细胞的tau传播中的作用。