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Passive Immunization in Alpha-Synuclein Preclinical Animal Models.

Jonas Folke1,2,3, Nelson Ferreira4, Tomasz Brudek2,3

  • 1Department of Geriatric Medicine, University Hospital Essen, 45147 Essen, Germany.

Biomolecules
|February 25, 2022
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Summary

Passive immunotherapy shows promise for alpha-synucleinopathies like Parkinson's disease. Targeting early protein forms and focusing on body-first diseases may improve treatment effectiveness in patients.

Keywords:
alpha-synucleindisease stratificationpassive immunization

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Area of Science:

  • Neuroscience
  • Immunology
  • Pathology

Background:

  • Alpha-synucleinopathies (e.g., Parkinson's disease) are progressive neurodegenerative disorders.
  • Pathological alpha-synuclein (αsyn) misfolding and accumulation drive disease progression.
  • Current therapies offer only symptomatic relief for motor and non-motor symptoms.

Purpose of the Study:

  • To review passive immunotherapy achievements in animal models of synucleinopathies.
  • To propose novel strategies for enhancing the translational success of immunotherapy in human studies.

Main Methods:

  • Review of preclinical passive immunotherapy studies targeting alpha-synuclein.
  • Analysis of factors limiting clinical trial efficacy.
  • Proposal of targeted antibody strategies and patient selection criteria.

Main Results:

  • Passive immunotherapy demonstrates potential in preclinical models by targeting alpha-synuclein.
  • Clinical trials show safety but reduced efficacy compared to animal studies.
  • Immature alpha-synuclein conformations and body-first synucleinopathies are identified as key targets.

Conclusions:

  • Targeting immature alpha-synuclein conformations (monomers, oligomers, protofibrils) may offer a more effective therapeutic approach.
  • Focusing on body-first synucleinopathies allows intervention before significant brain pathology develops.
  • These strategies could improve the translation of passive immunotherapy from animal models to human patients.