Alpha-synuclein Immunization Strategies for Synucleinopathies in Clinical Studies: A Biological Perspective

Abstract

The therapeutic strategies currently available for neurodegenerative diseases such as Parkinson’s disease target only the symptoms of the disease. Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy can be summarized as synucleinopathies, as they are all characterized by the aggregation and accumulation of alpha-synuclein (α-syn) in the brain. Targeting α-syn by its formation and progression opens a new and promising disease-modifying therapeutic strategy. Thus, several distinct immunotherapeutic approaches are currently being evaluated in clinical trials. The objective of this article is to review, from a biological perspective, the most important properties of these passive and active immunotherapies to point out their relevance and suitability for the treatment of synucleinopathies.

α-Synuclein oligomers and fibrils: partners in crime in synucleinopathies

“…Passive immunization is based on the administration of antibodies by specialized personnel; at the same time, this procedure guarantees the possibility to control systemic antibody concentrations and to interrupt treatment when side effects occur (Bergström et al, 2016). The largest majority of such antibodies are raised against small epitopes predominantly localized at the C-terminal domain of αS (Knecht et al, 2022). These approaches, targeting various αS epitopes, have shown neuroprotection in transgenic mouse models of PD, DLB, and MSA (Masliah et al, 2011;Mandler et al, 2015;Tran et al, 2014;Spencer et al, 2017;Henderson et al, 2020b;Lemos et al, 2020), thus leading to reduced accumulation of toxic oligomers and limited neurodegeneration.…”

“…These approaches, targeting various αS epitopes, have shown neuroprotection in transgenic mouse models of PD, DLB, and MSA (Masliah et al, 2011;Mandler et al, 2015;Tran et al, 2014;Spencer et al, 2017;Henderson et al, 2020b;Lemos et al, 2020), thus leading to reduced accumulation of toxic oligomers and limited neurodegeneration. Nevertheless, the existence of potential detrimental effects against physiological αS, as well as the logistical challenges related to the crossing of the blood-brain barrier must be considered (Knecht et al, 2022). Very recently, the first two phase II trials of therapies aimed at targeting αS in early PD did not pursue the primary endpoints.…”

Current Advances of Plant-Based Vaccines for Neurodegenerative Diseases

“…Remarkably, a number of studies have demonstrated that the immune system or its associated components could be exploited via immunotherapeutic strategies to target the key misfolded and aggregated proteins in NDDs, i.e., beta-amyloid (Aβ), tau, and α-synuclein (α-syn) [ 33 ]. In this sense, it has been suggested that antibodies, also called immunoglobulins (Igs), have notable potential as immunotherapeutic agents against NDDs (passive immunization) [ 34 , 35 , 36 ]. Similarly, peptide-based vaccines employing specific epitopes or peptides that mimic the structure of epitopes (mimotopes) are currently being developed to prevent and/or treat NDDs by harnessing the activity of the immune system (active immunization) [ 35 , 36 , 37 ].…”

“…In this sense, it has been suggested that antibodies, also called immunoglobulins (Igs), have notable potential as immunotherapeutic agents against NDDs (passive immunization) [ 34 , 35 , 36 ]. Similarly, peptide-based vaccines employing specific epitopes or peptides that mimic the structure of epitopes (mimotopes) are currently being developed to prevent and/or treat NDDs by harnessing the activity of the immune system (active immunization) [ 35 , 36 , 37 ]. As an example, in recent years a variety of vaccine designs for NDDs have been described, including MultiTEP-based vaccines, virus-like particle (VLP)-based vaccines, DNA-based vaccines, modified vaccinia virus Ankara (MVA) poxvirus-based vaccines, and synthetic peptide vaccines [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”

Robust nuclease-dead S. aureus dCas9-mediated alpha-synuclein knockdown in substantia nigra in a humanized mouse model of Parkinson’s disease

“…Conceptually, the reduction of alpha-synuclein protein levels has been a widely attempted therapeutic approach and the RNA and protein level with antisense oligonucleotides, small molecules and immune therapy 21 . Several immunotherapeutic CRISPR-mediated alpha-synuclein knockdown in vivo 4 approaches are currently being evaluated in clinical trials 22,23 . Small molecules and antisense oligonucleotides that disaggregate toxic alpha-synuclein species or destroy alpha-synuclein mRNA are in late-stage preclinical programs 24 .…”