Translational therapies for multiple system atrophy: Bottlenecks and future directions

Over the last decade a prominent amount of studies in preclinical transgenic models of multiple system atrophy (MSA) has been performed. These studies have helped understand mechanisms downstream to the α-synuclein oligodendroglial accumulation relevant to human MSA. However, the successful translation of the preclinical outcomes into a clinical trial has failed. Looking back, we can now identify possible confounders for the failure. Biomarkers of disease progression are mostly missing. Early diagnosis and initiation of therapeutic clinical trials is limited. The need of both proof-of-concept as well as clinically relevant preclinical study designs with clinically relevant timing and preclinical readouts is identified as a must in our translational efforts for MSA to date. Finally, improved clinical study designs with improved enrollment criteria, and measurement outcomes are warranted on the way to finding the successful therapeutic approach for MSA. This review provides an overview of experimental studies and clinical trials for MSA and the lessons learned over the last decade towards the identification of the cure for MSA.