title: 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 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-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 α-syn and discovered a novel set of AFF that identified α-syn oligomers. Next, the peptide that elicited the most specific response against α-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-α-syn tg mice. Vaccination with AFF 1 resulted in high antibody titers in CSF and plasma, which crossed into the CNS and recognized α-syn aggregates. Active vaccination with AFF 1 resulted in decreased accumulation of α-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 α-syn involved activation of microglia and increased anti-inflammatory cytokine expression, further supporting the efficacy of this novel active vaccination approach for synucleinopathies.
authors: AFFiRiS AG, Vienna Biocenter, 1030, Vienna, Austria, markus.mandler@affiris.com.
authors: Markus
authors: M
authors: Mandler
authors: Elvira
authors: E
authors: Valera
authors: Edward
authors: E
authors: Rockenstein
authors: Harald
authors: H
authors: Weninger
authors: Christina
authors: C
authors: Patrick
authors: Anthony
authors: A
authors: Adame
authors: Radmila
authors: R
authors: Santic
authors: Stefanie
authors: S
authors: Meindl
authors: Benjamin
authors: B
authors: Vigl
authors: Oskar
authors: O
authors: Smrzka
authors: Achim
authors: A
authors: Schneeberger
authors: Frank
authors: F
authors: Mattner
authors: Eliezer
authors: E
authors: Masliah
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood / Q000134:cerebrospinal fluid; D001369:Axons / Q000473:pathology / Q000502:physiology; D002421:Caudate Nucleus / Q000473:pathology / Q000503:physiopathology; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D006801:Humans; D020961:Lewy Body Disease / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008569:Memory Disorders / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D011699:Putamen / Q000473:pathology / Q000503:physiopathology; D013569:Synapses / Q000473:pathology / Q000502:physiology; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D014611:Vaccination / Q000379:methods*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D000906:Antibodies; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051844:alpha-Synuclein