LAUSR

Alpha-synuclein (α-syn) aggregates are the hallmark pathological inclusions of Parkinson’s disease (PD). Even though its mechanisms of action are still unclear, multiple pathways of cellular dysfunction in models of α-syn toxicity have been described, and it is acknowledged that buildup of the misfolded α-syn aggregates hinders cell communication, causing neuronal degeneration. Encouraging preliminary evidence showed a significant lowering of α-syn plasma levels and cerebrospinal fluid penetration of monoclonal antibodies against α-syn. Moreover, passive immunotherapy offers the opportunity to deliver directly precise concentrations of monoclonal antibodies without requiring an immune response to generate an antibody response. Two similarly designed phase II trials using different humanized anti-α-syn antibodies were recently reported. Both multicenter, randomized, double-blinded trials recruiting patients with early-stage PD (Hoehn and Yahr stage <3) with abnormal dopamine transporter (DaT) scans demonstrated a good safety profile, but neither met the primary or secondary end points, represented by the change in the Movement Disorder Society– sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score and changes in DaT imaging over a 52-week period, respectively. However, there was the suggestion of a slower progression with the lower dose on the MDS-UPDRS Part III in the PASADENA study, which led to the launch of a phase IIb study. There is a strong scientific rationale in targeting aggregated forms of α-syn. Indeed, the identification of mutations in the α-syn gene leading to PD and the evidence of α-syn aggregates as a major component of Lewy bodies support the hypothesis that α-syn is a key player in the disease. Nevertheless, several mechanisms have been implicated in PD pathogenesis and not all could be linked to α-syn toxicity. PARK2 and LRRK2-related PD may occur independently of α-syn aggregation, and insights from late-onset familial parkinsonism suggest that Lewy bodies might more likely be a consequence than a cause of parkinsonism. In addition, because nigral neuronal loss has been demonstrated to occur before the presence of α-syn, neither the MDS-UPDRS Part III or DaT imaging may be fully appropriate to reflect α-syn toxicity. Finally, both the full extent of the physiological function for α-syn and the nature of its toxic species have yet to be elucidated. In this context, the positive results in secondary end points of antibodies against the C terminus of α-syn in the PASADENA study are encouraging and could suggest a more efficacious target engagement. This, along with using a longer time window to assess the primary end point in future α-syn antibody trials-perhaps on late manifestations such as dementia incidence-might be a worthwhile future step needed to test whether passive immunotherapy targeting α-syn can be clinically useful.