LAUSR

I was interested to read two distinctly different Viewpoint assessments of the recent publications describing the failure of first two anti-α-synuclein (AS) monoclonal antibody trials in Parkinson’s disease (PD) to demonstrate clinical efficacy on their primary outcome variables (the motor Part III of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale [MDS-UPDRS]). The first of these Viewpoints, in Journal of the American Medical Association (JAMA) Neurology, emphasized the importance of a “loss-of-function” basis for neurodegenerative diseases and remarkably concluded “We do not need more anti-synuclein trials,” despite the fact that the two trials in question are the only trials of any anti-synuclein therapy for PD completed to date and they are limited to a single treatment mechanism of action. The more recent Viewpoint, published in this journal, highlighted reasons for optimism, emphasizing that this is just the beginning of AS-based therapeutics. From my perspective, one should probably not consider the pathogenic mechanisms underlying PD and other neurodegenerative diseases as “all or none” gain-of-function (ie, toxic proteinopathies) or loss-of-function processes. However, even the most careful and thorough evaluation of the literature supporting a potential role for loss-of-function of AS (eg, related to its pre-synaptic role in SNARE-complex assembly, neurotransmitter release, and synaptic vesicle pool homeostasis) accepts the critical importance of a toxic gain-of-function on multiple cellular pathways impacting on the progressive neurodegeneration. The Viewpoint by Jensen and colleagues, nicely summarized the evidence for this factor, but also highlighted the need for anti-AS therapeutic approaches to avoid excessively reducing the levels of physiological AS species (ie, potentially aggravating any loss-of-function contribution). The authors also carefully reviewed the various pitfalls faced by trials of anti-AS therapies in attempting to establish effective disease modifying therapy (DMT) for PD. I would like to add a couple of supplementary comments to their excellent summary. The common concern that DMTs in PD have not been conducted long enough to show the impact of the therapeutic may especially apply to monoclonal antibodies, which are largely directed at the extracellular species of the protein at the time of cell-to-cell spread. In PD, the concept of a prionlike spread of toxic species of AS was first largely considered and supported by the discovery of Lewy bodies in fetal neurons in patients who had undergone fetal nigral transplantation. It is important to point out, however, that pathological forms of AS were not found in these neurons until well after 4 years of follow-up and so relatively short trials directed exclusively at this one aspect of the role of AS in the pathogenesis of human PD may have been doomed to failure from the start. Another issue that needs to be considered is the fact that clinical DMT trials traditionally enroll patients with early disease not requiring symptomatic therapy and follow the progressive motor decline on the MDS-UPDRS as the primary outcome variable. It is important to acknowledge that the worsening of parkinsonism experienced by these patients over the course of the first several years of disease is largely related to progressive loss of presynaptic nigrostriatal dopamine. However, once the substantia nigra has been impacted by the disease process (with all of the reasons summarized by Jensen et al for a toxic effect of AS playing an important role), we have no idea whether the progressive nigrostriatal dying back process accounting for the progression of early signs and symptoms relates to further nigral cell-to-cell spread of AS or whether this spread has largely been completed. Further, we do not know the extent to which the progressive nigrostriatal dysfunction relates to ongoing effects of toxic AS species versus the possibility that these have triggered now independent and self-perpetuating cellular pathway disturbances, some of which may be more relevant to dopaminergic than other neurones affected later in the course of the disease. Advances in our understanding of the pathogenesis of PD, including a better appreciation of the relative timing of various processes and whether they occur in series, in parallel, or a combination, will be critical if we are to realize the goal of developing successful DMT in PD. As Jensen et al commented, it is very likely that combination therapies will be required as in oncology, and I would predict that this may even combine anti-AS therapies that target different aspects of its translation, deposition, aggregation, or cell-to-cell transmission. Indeed, this could be the place that passive immunization with antisynuclein monoclonal antibodies plays in the long-term application of anti-synuclein therapies. © 2023 International Parkinson and Movement Disorder Society.