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Amyloid-β and α-synuclein immunotherapy: from experimental studies to clinical trials

Amyloid-β and α-synuclein immunotherapy: from experimental studies to clinical trials
Amyloid-β and α-synuclein immunotherapy: from experimental studies to clinical trials
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.
Alzheimer’s disease, Parkinson’s disease, amyloid-β, animal models, immunotherapy, neurodegenerative disease, α-synuclein
1662-4548
Nimmo, Jacqui, Taryn
222608e3-256e-4ba4-a259-cbdfcb5340c6
Kelly, Louise
a73e3582-a03e-492f-b164-bf1de4b7600d
Verma, Ajay
87adfc69-4702-4792-8a59-5aa007e47427
Carare, Roxana-Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Dodart, Jean-Cosme
042937d4-d3a6-4e37-9274-d1b90ee33c59
Nimmo, Jacqui, Taryn
222608e3-256e-4ba4-a259-cbdfcb5340c6
Kelly, Louise
a73e3582-a03e-492f-b164-bf1de4b7600d
Verma, Ajay
87adfc69-4702-4792-8a59-5aa007e47427
Carare, Roxana-Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Dodart, Jean-Cosme
042937d4-d3a6-4e37-9274-d1b90ee33c59

Nimmo, Jacqui, Taryn, Kelly, Louise, Verma, Ajay, Carare, Roxana-Octavia, Nicoll, James and Dodart, Jean-Cosme (2021) Amyloid-β and α-synuclein immunotherapy: from experimental studies to clinical trials. Frontiers in Neuroscience, 15 (733857), [733857]. (doi:10.3389/fnins.2021.733857).

Record type: Review

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.

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Published date: 1 September 2021
Additional Information: Funding Information: Funding. This review has been supported by the Ph.D. studentship from United Neuroscience. United Neuroscience also supported preclinical experiments related to UB-311 and UB-312. Funding Information: This review has been supported by the Ph.D. studentship from United Neuroscience. United Neuroscience also supported preclinical experiments related to UB-311 and UB-312. Publisher Copyright: © Copyright © 2021 Nimmo, Kelly, Verma, Carare, Nicoll and Dodart. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
Keywords: Alzheimer’s disease, Parkinson’s disease, amyloid-β, animal models, immunotherapy, neurodegenerative disease, α-synuclein

Identifiers

Local EPrints ID: 452796
URI: http://eprints.soton.ac.uk/id/eprint/452796
ISSN: 1662-4548
PURE UUID: 4a4963b3-4f3c-41fe-afbb-1f9c407c66ea
ORCID for Roxana-Octavia Carare: ORCID iD orcid.org/0000-0001-6458-3776
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246

Catalogue record

Date deposited: 20 Dec 2021 17:51
Last modified: 14 Jan 2023 02:38

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Contributors

Author: Jacqui, Taryn Nimmo
Author: Louise Kelly
Author: Ajay Verma
Author: James Nicoll ORCID iD
Author: Jean-Cosme Dodart

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