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 a α-syn specific T-cell response. This approach allows the generation 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 mouse models of PD and Dementia with Lewy bodies (DLB), 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 that was 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.

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…These results suggested that α-syn vaccination is effective in reducing neuronal accumulation of α-syn aggregates and that further development of this approach might have a potential role in the treatment of synucleinopathies. Other active immunization approaches using AFFITOPEs (AFFiRiS AG) that mimic abnormal conformations of α-syn have been studied in animals model of PD and MSA [65,66]. AFFITOPEs that mimic the C-terminus region of α-syn are able to elicit an immune response specific to α-syn oligomers [66].…”

“…Other active immunization approaches using AFFITOPEs (AFFiRiS AG) that mimic abnormal conformations of α-syn have been studied in animals model of PD and MSA [65,66]. AFFITOPEs that mimic the C-terminus region of α-syn are able to elicit an immune response specific to α-syn oligomers [66]. Vaccination with one of these AFFITOPEs (AFF 1) resulted in high antibody titers against α-syn aggregates, decreased accumulation of α-syn oligomers, reduced degeneration of tyrosine hydroxylase fibers in the caudoputamen nucleus, and improved motor and memory deficits in 2 α-syn transgenic models [66].…”

“…AFFITOPEs that mimic the C-terminus region of α-syn are able to elicit an immune response specific to α-syn oligomers [66]. Vaccination with one of these AFFITOPEs (AFF 1) resulted in high antibody titers against α-syn aggregates, decreased accumulation of α-syn oligomers, reduced degeneration of tyrosine hydroxylase fibers in the caudoputamen nucleus, and improved motor and memory deficits in 2 α-syn transgenic models [66]. Moreover, when administered to a transgenic model of MSA, AFF 1 also induced a reduction in neurodegeneration and demyelination in neocortex, striatum, and corpus callosum [65].…”

“…Moreover, antibodies against these proteins can regulate inflammation and facilitate the clearance of target proteins via autophagy or microglia (Fig. 2) [61][62][63][64][65][66]. Neurodegenerative diseases are associated with signs of chronic neuroinflammation and elevated levels of several Fig.…”

“…Microgliosis, astrogliosis, and peripheral immune infiltration contribute to the cognitive and motor deficits, and lead to a toxic increase in the levels of reactive oxygen species [68], and to secondary neurodegeneration, characteristic of late disease stages [69]. Immunotherapy has been shown to induce a physiological microglial response (M2 type) and reduce the production of proinflammatory cytokines [65,66], thus exerting an anti-inflammatory effect in neurodegenerative disorders [70,71]. However, among the disadvantages of immunotherapy are the potential for autoimmune responses, nonspecific inflammatory reactions such as perivascular edema, need for repetitive administration, lack of response due to senescence of the innate immune system, and limited penetration of antibodies into the central nervous system.…”