Disease-modifying therapies for Parkinson disease: lessons from multiple sclerosis

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide only symptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs. Major advances have been made in disease-modifying therapies for multiple sclerosis, but people with Parkinson disease still lack such treatment options. Drawing on discussions from a symposium held in November 2022, this Roadmap proposes areas for exploration in Parkinson disease using lessons learned from therapeutic development in multiple sclerosis. At least 18 disease-modifying therapies (DMTs) have been approved for relapsing multiple sclerosis (MS), and the first DMT for primary progressive MS was recently approved; by contrast, no DMTs are available for Parkinson disease (PD).Further investigation into risk loci identified from genome-wide association studies and research into the immune system as a link between the CNS and gut microbiota are anticipated to reveal novel targets for DMTs in PD and MS.Both the PD and MS fields require preclinical models, including animal models and patient-derived induced pluripotent stem cell-based models, that capture a range of aetiological and pathobiological factors.MRI and alpha-synuclein seed amplification assays are allowing identification of prodromal stages of MS and PD, respectively. Trials in patients with radiologically isolated syndrome have provided evidence for benefits of DMT interventions during the very early stages of MS.PD and MS are complicated by heterogeneous clinical presentations, and subtyping of these diseases according to clinical features has limitations that might be overcome by classification systems based on pathobiological molecular mechanisms.The ability to assess treatment efficacy with MRI has been instrumental in DMT development for relapsing MS; similarly, reliable outcome measures for progressive MS and PD are still lacking.