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Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials.

ABSTRACT: Immunotherapeutic approaches are currently in the spotlight for their potential as disease-modifying treatments for neurodegenerative disorders. The discovery that ?-synuclein (?-syn) can transmit from cell to cell in a prion-like fashion suggests that immunization might be a viable option for the treatment of synucleinopathies. This possibility has been bolstered by the development of next-generation active vaccination technology with short peptides-AFFITOPEs(®) (AFF)- that do not elicit an ?-syn-specific T cell response. This approach allows for the production of long term, sustained, more specific, non-cross reacting antibodies suitable for the treatment of synucleinopathies, such as Parkinson's disease (PD). In this context, we screened a large library of peptides that mimic the C-terminus region of ?-syn and discovered a novel set of AFF that identified ?-syn oligomers. Next, the peptide that elicited the most specific response against ?-syn (AFF 1) was selected for immunizing two different transgenic (tg) mouse models of PD and Dementia with Lewy bodies, the PDGF- and the mThy1-?-syn tg mice. Vaccination with AFF 1 resulted in high antibody titers in CSF and plasma, which crossed into the CNS and recognized ?-syn aggregates. Active vaccination with AFF 1 resulted in decreased accumulation of ?-syn oligomers in axons and synapses, accompanied by reduced degeneration of TH fibers in the caudo-putamen nucleus and by improvements in motor and memory deficits in both in vivo models. Clearance of ?-syn involved activation of microglia and increased anti-inflammatory cytokine expression, further supporting the efficacy of this novel active vaccination approach for synucleinopathies.

SUBMITTER: Mandler M

PROVIDER: S-EPMC4034750 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials.

Mandler Markus M Valera Elvira E Rockenstein Edward E Weninger Harald H Patrick Christina C Adame Anthony A Santic Radmila R Meindl Stefanie S Vigl Benjamin B Smrzka Oskar O Schneeberger Achim A Mattner Frank F Masliah Eliezer E

Acta neuropathologica 20140214 6

Immunotherapeutic approaches are currently in the spotlight for their potential as disease-modifying treatments for neurodegenerative disorders. The discovery that α-synuclein (α-syn) can transmit from cell to cell in a prion-like fashion suggests that immunization might be a viable option for the treatment of synucleinopathies. This possibility has been bolstered by the development of next-generation active vaccination technology with short peptides-AFFITOPEs(®) (AFF)- that do not elicit an α-s ...[more]

PMID: 24525765

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Dataset Information

Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials.

Publications

Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials.

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