Abstract
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.
Highlights
From the development of the first vaccine against smallpox in 1796, immunisation has led to the worldwide reduction and eradication of numerous diseases
The main challenge in vaccine design is overcoming immune tolerance to self-antigens while avoiding autoimmunity. This can partly be remedied by designing vaccines that selectively target misfolded protein conformations and not the healthy protein, and immunotherapies that have incorporated such designs have been reviewed in detail (Plotkin and Cashman, 2020)
A consequence of amyloid-β immunotherapy in the brain is the occurrence of vasogenic edema (VE) or microhaemorrhages, which are associated with the vascular amyloid
Summary
From the development of the first vaccine against smallpox in 1796, immunisation has led to the worldwide reduction and eradication of numerous diseases. Over the last 30 years, immunisation has advanced beyond the treatment of infectious diseases to applications within cancer therapy and neurodegenerative disease (Jing et al, 2016; Panza et al, 2019; Zella et al, 2019; Plotkin and Cashman, 2020)
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