Dissecting the Heterogeneous Molecular Mechanisms Underlying Multiple Sclerosis Progression

Abstract Multiple sclerosis is the most common cause of non-traumatic disability in young adults, with an estimated total economic burden of $85.4 billion. Irreversible disability accumulation is the most challenging, unmet need in care for people with multiple sclerosis (pwMS) and drives socioeconomic burden. Disability accumulates in two different clinical contexts: Progression independent of relapse activity (PIRA, ~ 80%) and relapse-associated worsening (RAW, ~20%). Both are driven by a complex interplay of immune- and non- immune processes. Body fluid biomarkers offer a unique opportunity to disentangle the complicated pathophysiology of progression, which cannot be studied with sufficient fidelity in vitro or using animal models. I spearheaded a collaboration between US and European cohorts with > 12,000 visits to assess neuroaxonal injury in pwMS. This work revealed that central nervous system (CNS) injury occurred months to years preceding progression (pre-PIRA/ pre-RAW). Building upon this research, the primary objective of this grant is to elucidate the cellular constituents and related mechanisms of CNS injury during pre-progression. To that end, I plan to acquire the skills and tools to perform a proteome-wide analysis of serum samples from two international cohorts from the US and Germany. The Olink® Explore HT kit can measure up to 5400 proteins using antibody-based proximity extension technology. Among those proteins are many CNS-driven markers that cannot be measured otherwise. This proteomic analysis will help us determine the magnitude of astrocyte response during pre-PIRA, define the severity and dynamics of oligodendrocyte and myelin injury in pre-PIRA and how it relates to neuroaxonal injury and characterize the role of synaptic injury during that critical window of CNS injury (Aim 1). The dataset generated during Aim 1 will be further analyzed in Aims 2 and 3 to define the driving mechanisms of PIRA at different disease stages, how PIRA differs from RAW, and what distinct markers can characterize each process. This project is anticipated to unravel a set of proteins/ protein pathways of particular significance for MS progression. In my future independently funded lab, I aim to build on this work by establishing the next-stage progression-focused assays and defining their clinical context of use in MS.