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Immunization targeting diseased proteins in synucleinopathy and tauopathy : insights from clinical trials

Zhan, Xiaoni LU ; Wen, Gehua LU orcid ; Wu, Xu and Li, Jia-Yi LU (2025) In Translational Neurodegeneration 14. p.1-38
Abstract

Synucleinopathies and tauopathies are neurodegenerative disorders characterized by the pathological accumulation of α-synuclein (α-syn) and tau proteins, respectively. These disorders are traditionally managed with symptomatic treatments without addressing the underlying pathologies. Recent advancements in passive immunotherapies, notably the FDA approval of the amyloid-beta (Aβ)-targeting antibody lecanemab, have sparked new hope in directly targeting pathological proteins. However, unlike the extracellular Aβ pathology, immunotherapies aimed at α-syn and tau, which predominantly form intracellular inclusions, face substantial challenges. To date, the therapeutic efficacy of five α-syn and 14 tau antibodies has been assessed in... (More)

Synucleinopathies and tauopathies are neurodegenerative disorders characterized by the pathological accumulation of α-synuclein (α-syn) and tau proteins, respectively. These disorders are traditionally managed with symptomatic treatments without addressing the underlying pathologies. Recent advancements in passive immunotherapies, notably the FDA approval of the amyloid-beta (Aβ)-targeting antibody lecanemab, have sparked new hope in directly targeting pathological proteins. However, unlike the extracellular Aβ pathology, immunotherapies aimed at α-syn and tau, which predominantly form intracellular inclusions, face substantial challenges. To date, the therapeutic efficacy of five α-syn and 14 tau antibodies has been assessed in patients with synucleinopathies and tauopathies. These immunizations have demonstrated promising preclinical outcomes in alleviating pathological and behavioral deficits, but have not yielded significant clinical improvements in symptoms or measurable biomarkers. Therefore, a clear understanding of potential causes for the discrepancies between preclinical successes and clinical outcomes is critical for the successful translation of immunotherapy in the future. In this review, we examine existing passive immunotherapeutic strategies targeting α-syn and tau, specifically in patients with Alzheimer's disease and Parkinson's disease. Lessons learned from initial trial failures are also discussed, including refinement of animal models, inclusion and stratification of participants, improvement of clinical evaluations, and development of biomarkers. Given the overlapping pathologies and clinical manifestations of synucleinopathies and tauopathies, we further explore the potential of combined therapies targeting co-pathologies, offering novel insights for future therapeutic development against these neurodegenerative disorders.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Tauopathies/therapy, tau Proteins/immunology, Synucleinopathies/therapy, Clinical Trials as Topic, alpha-Synuclein/immunology, Animals, Immunotherapy/methods
in
Translational Neurodegeneration
volume
14
article number
33
pages
1 - 38
publisher
BioMed Central (BMC)
external identifiers
  • pmid:40588759
ISSN
2047-9158
DOI
10.1186/s40035-025-00490-9
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
00b11fe4-d843-4c2b-b627-994e56a13cd3
date added to LUP
2025-10-03 13:36:05
date last changed
2025-10-03 13:36:05
@article{00b11fe4-d843-4c2b-b627-994e56a13cd3,
  abstract     = {{<p>Synucleinopathies and tauopathies are neurodegenerative disorders characterized by the pathological accumulation of α-synuclein (α-syn) and tau proteins, respectively. These disorders are traditionally managed with symptomatic treatments without addressing the underlying pathologies. Recent advancements in passive immunotherapies, notably the FDA approval of the amyloid-beta (Aβ)-targeting antibody lecanemab, have sparked new hope in directly targeting pathological proteins. However, unlike the extracellular Aβ pathology, immunotherapies aimed at α-syn and tau, which predominantly form intracellular inclusions, face substantial challenges. To date, the therapeutic efficacy of five α-syn and 14 tau antibodies has been assessed in patients with synucleinopathies and tauopathies. These immunizations have demonstrated promising preclinical outcomes in alleviating pathological and behavioral deficits, but have not yielded significant clinical improvements in symptoms or measurable biomarkers. Therefore, a clear understanding of potential causes for the discrepancies between preclinical successes and clinical outcomes is critical for the successful translation of immunotherapy in the future. In this review, we examine existing passive immunotherapeutic strategies targeting α-syn and tau, specifically in patients with Alzheimer's disease and Parkinson's disease. Lessons learned from initial trial failures are also discussed, including refinement of animal models, inclusion and stratification of participants, improvement of clinical evaluations, and development of biomarkers. Given the overlapping pathologies and clinical manifestations of synucleinopathies and tauopathies, we further explore the potential of combined therapies targeting co-pathologies, offering novel insights for future therapeutic development against these neurodegenerative disorders.</p>}},
  author       = {{Zhan, Xiaoni and Wen, Gehua and Wu, Xu and Li, Jia-Yi}},
  issn         = {{2047-9158}},
  keywords     = {{Humans; Tauopathies/therapy; tau Proteins/immunology; Synucleinopathies/therapy; Clinical Trials as Topic; alpha-Synuclein/immunology; Animals; Immunotherapy/methods}},
  language     = {{eng}},
  month        = {{07}},
  pages        = {{1--38}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Translational Neurodegeneration}},
  title        = {{Immunization targeting diseased proteins in synucleinopathy and tauopathy : insights from clinical trials}},
  url          = {{http://dx.doi.org/10.1186/s40035-025-00490-9}},
  doi          = {{10.1186/s40035-025-00490-9}},
  volume       = {{14}},
  year         = {{2025}},
}