Passive Immunization in Alpha-Synuclein Preclinical Animal Models

Abstract

Alpha-synucleinopathies include Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. These are all progressive neurodegenerative diseases that are characterized by pathological misfolding and accumulation of the protein alpha-synuclein (αsyn) in neurons, axons or glial cells in the brain, but also in other organs. The abnormal accumulation and propagation of pathogenic αsyn across the autonomic connectome is associated with progressive loss of neurons in the brain and peripheral organs, resulting in motor and non-motor symptoms. To date, no cure is available for synucleinopathies, and therapy is limited to symptomatic treatment of motor and non-motor symptoms upon diagnosis. Recent advances using passive immunization that target different αsyn structures show great potential to block disease progression in rodent studies of synucleinopathies. However, passive immunotherapy in clinical trials has been proven safe but less effective than in preclinical conditions. Here we review current achievements of passive immunotherapy in animal models of synucleinopathies. Furthermore, we propose new research strategies to increase translational outcome in patient studies, (1) by using antibodies against immature conformations of pathogenic αsyn (monomers, post-translationally modified monomers, oligomers and protofibrils) and (2) by focusing treatment on body-first synucleinopathies where damage in the brain is still limited and effective immunization could potentially stop disease progression by blocking the spread of pathogenic αsyn from peripheral organs to the brain.

Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies

“…Antibodies could be tailored to combat uptake and propagation of a certain disease-specific asyn strain. If multiple dominant strains would be detected in a patient, treatment may require a personalized cocktail of several antibodies (Folke et al, 2022 ). Thus, the ability of the LCO-assay to differentiate morphotypes of aggregated asyn in easily accessible tissue and fluids would allow personalized treatment at early phases of disease, potentially prior to autonomic and CNS damage, altogether highlighting the importance of this assay in early disease-specific diagnosis.…”

“…Disease-modifying treatment strategies such as immunotherapy have been suboptimal in clinical trials compared to preclinical conditions, as described by Folke et al ( 2022 ). The authors discuss that screening of antibody-treatment in brain-first only LBD models as well as suboptimal patient selection in clinical trials, may have contributed to disappointing translational results.…”

“…These asyn aggregates can spread through synaptically coupled networks along the brain-body axis and ultimately result in widespread neurodegeneration in the central nervous system (CNS) and in multiple peripheral organs (Beach et al, 2010 ; Chiang and Lin, 2019 ; Mendoza-Velásquez et al, 2019 ). The clinical representation of PD, DLB, PAF, and MSA patients is highly heterogeneous and overlapping during the early disease stages (Palermo et al, 2020 ; Berg et al, 2021 ; Folke et al, 2022 ). Due to the variable involvement of different neuronal systems, each synucleinopathy may include a wide range of motor, cognitive, gut and other autonomic deficits, up to 20 years prior to diagnosis, complicating early and accurate diagnosis.…”

“…The identification and characterization of disease-specific asyn aggregates in easily accessible peripheral fluids or tissues may enable early stratification as well as development of subtype-specific targets for therapeutic strategies. Especially in immunotherapy, target biology should be optimized toward strain-specific pathology (Folke et al, 2022 ). For this purpose, it is crucial to gain insight in the different structural characteristics of asyn strains underlying different synucleinopathies.…”

Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease

“…An additional interesting tactic would be using the results from this study and others, not only for biomarker potential, but also in the debate regarding passive immunization candidates for synucleinopathies. Most candidates are of the IgG1 subclass [ 42 ]. The present results and previous reports show that especially MSA have increased IgG1 anti-αSyn nAbs in plasma and IgG1 and IgG3 in CSF [ 20 , 21 ].…”