Immunization therapies for Parkinson's disease: state of the art and considerations for future clinical trials

Introduction Advances in the understanding of the mechanisms that lead to Lewy body pathology in Parkinson's disease (PD) have yielded rationales for tackling neurodegeneration associated with alpha-Synuclein (alpha-Syn) misfolding, aggregation, and/or its related spreading. Immunization therapies targeting distinct alpha-Syn epitopes (conformational and linear) that aim to limit extracellular spread in the brain are now in development. Completed and ongoing studies have enrolled early PD patients without considering individual clinical differences and assume a common pathogenetic mechanism of the disease. Such approaches have led to disappointing results; this is most likely attributed to trial methodology and inadequate patient selection rather than underlying target biology. Areas covered This review presents the status of immunotherapies that target alpha-Syn epitopes in PD. Mechanisms associated with neurodegeneration are examined along with the limitations of current antibody research strategies and ongoing clinical trials. Patient stratification based on disease progression is discussed and the article culminates with author suggestions on how to progress future clinical trials. Expert opinion The efficacy of passive and active immunotherapies is inadequately evaluated in ongoing clinical trials where participating patients have various progression rates, genetic backgrounds, and clinical phenotypes. Future disease-modifying studies can overcome these limitations by enrolling patients based on progression pathways and genotypic contribution to disease manifestations.