Nimmo Jacqui Taryn, Kelly Louise, Verma Ajay, Carare Roxana O, Nicoll James A R, Dodart Jean-Cosme
Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
Yumanity Therapeutics, Boston, MA, United States.
Front Neurosci. 2021 Sep 1;15:733857. doi: 10.3389/fnins.2021.733857. eCollection 2021.
Alzheimer's disease and Lewy body diseases are the most common causes of neurodegeneration and dementia. Amyloid-beta (Aβ) and alpha-synuclein (αSyn) are two key proteins involved in the pathogenesis of these neurodegenerative diseases. Immunotherapy aims to reduce the harmful effects of protein accumulation by neutralising toxic species and facilitating their removal. The results of the first immunisation trial against Aβ led to a small percentage of meningoencephalitis cases which revolutionised vaccine design, causing a shift in the field of immunotherapy from active to passive immunisation. While the vast majority of immunotherapies have been developed for Aβ and tested in Alzheimer's disease, the field has progressed to targeting other proteins including αSyn. Despite showing some remarkable results in animal models, immunotherapies have largely failed final stages of clinical trials to date, with the exception of Aducanumab recently licenced in the US by the FDA. Neuropathological findings translate quite effectively from animal models to human trials, however, cognitive and functional outcome measures do not. The apparent lack of translation of experimental studies to clinical trials suggests that we are not obtaining a full representation of the effects of immunotherapies from animal studies. Here we provide a background understanding to the key concepts and challenges involved in therapeutic design. This review further provides a comprehensive comparison between experimental and clinical studies in Aβ and αSyn immunotherapy and aims to determine the possible reasons for the disconnection in their outcomes.
阿尔茨海默病和路易体病是神经退行性变和痴呆最常见的病因。淀粉样β蛋白（Aβ）和α-突触核蛋白（αSyn）是参与这些神经退行性疾病发病机制的两种关键蛋白。免疫疗法旨在通过中和毒性物质并促进其清除来减轻蛋白质积聚的有害影响。首次针对Aβ的免疫试验结果导致了一小部分脑膜脑炎病例，这彻底改变了疫苗设计，使免疫疗法领域从主动免疫转向了被动免疫。虽然绝大多数免疫疗法是针对Aβ开发的，并在阿尔茨海默病中进行了测试，但该领域已发展到针对包括αSyn在内的其他蛋白质。尽管在动物模型中显示出一些显著结果，但迄今为止，免疫疗法在临床试验的最后阶段大多失败了，不过最近美国食品药品监督管理局（FDA）批准的阿杜卡奴单抗除外。神经病理学发现从动物模型到人体试验的转化相当有效，然而，认知和功能结局指标却并非如此。实验研究明显缺乏向临床试验的转化，这表明我们从动物研究中并未完全了解免疫疗法的效果。在此，我们提供了对治疗设计中关键概念和挑战的背景理解。本综述进一步全面比较了Aβ和αSyn免疫疗法的实验研究和临床研究，并旨在确定它们结果不一致的可能原因。
