Mapping the Molecular Landscape of MS: A Multiomics Approach Uncovers New Drug Targets

Despite decades of research, multiple sclerosis (MS) remains an incurable, immune-mediated neurological disease, particularly resistant to treatment in its progressive forms. Now, a large-scale study led by Xia Jiang and colleagues has identified 18 potential causal proteins linked to MS, offering fresh insight into disease mechanisms and novel avenues for both drug discovery and repurposing.

By integrating proteomic, transcriptomic, and genomic datasets from plasma and brain tissues, the researchers prioritized nine proteins in each compartment as promising therapeutic targets. Their approach combined proteome-wide association studies (PWAS) with summary-based Mendelian randomization (SMR), followed by rigorous statistical validation using HEIDI testing and Bayesian colocalization. This pipeline distinguished truly causal relationships from coincidental genetic linkages.

Among the identified proteins, some are associated with increased MS risk (e.g., CR1, WARS in plasma; HLA-B, TRAF3 in brain), while others appear protective (e.g., CD59, TYMP, ICA1L). Many of these targets had not been previously implicated in MS, representing a significant expansion of the known therapeutic landscape.

Importantly, the study did not stop at genetic associations. It traced protein expression back to mRNA levels, using both bulk and single-cell transcriptomic datasets. This revealed that six of the prioritized targets—two from bulk mRNA data and four from MS-relevant cell types—exhibited consistent expression patterns, reinforcing their biological relevance. For example, ARHGAP1 and TNFRSF1A showed reduced expression in blood-derived T cells and granulocytes in MS patients, while AUH and ICA1L were downregulated in brain-resident cell types such as oligodendrocytes and astrocytes.

The study also performed protein–protein interaction (PPI) analyses, identifying intricate networks between seven of the new targets and 19 existing MS drug targets. This not only strengthens the biological plausibility of the findings but also illuminates potential combination therapies or synergistic effects. Notably, proteins such as TNFRSF1A and TRAF3 displayed cross-compartment interactions—suggesting that circulating proteins could influence neuroinflammatory processes in the central nervous system.

Beyond novel discovery, the research emphasized drug repurposing. Six of the 18 targets are already modulated by existing non-MS drugs. For instance, TYMP and WARS are targeted by fluoropyrimidine-class chemotherapeutics like capecitabine and trifluridine, while MTHFR interacts with accessible compounds such as vitamin B12 and folate. These latter nutrients, long speculated to support neurological health, now gain molecular validation as potential adjunct therapies in MS.

Two proteins stood out as particularly promising: HLA-B, part of the MHC class I complex, has previously been linked to protective MS alleles and shows strong interaction with HLA-DRB1, a major genetic risk locus; and TRAF3, a regulator of NF-κB signaling implicated in autoimmune inflammation. Both displayed causal associations in brain tissue and are embedded in immune and antiviral signaling pathways relevant to MS pathogenesis.

While the study presents a powerful framework for target prioritization, the authors caution against overinterpretation. Not all proteins have detectable pQTLs, and the findings require experimental validation. Still, this multiomics approach sets a new standard for identifying causally relevant and druggable targets in complex diseases like MS.

By bridging molecular layers—from genes to transcripts to proteins—and integrating large-scale datasets across tissues, this study exemplifies the potential of precision medicine to accelerate therapeutic innovation. As the authors conclude, such integrative strategies not only enhance our understanding of MS but may shorten the path from discovery to treatment.