Dissection of the BAFF pathway in Multiple Sclerosis with a view toward more specific and effective therapies

Summary Genome-wide association studies (GWAS) of multiple sclerosis (MS) have identified hundreds of susceptibility regions of the genome. Unfortunately, only in a few cases the causal gene and related mechanism have been identified. Coincident associations of DNA variants affecting both autoimmune disease risk and related immunophenotypes provide an informative route to dissect disease mechanism and identify drug targetable pathways. Using this approach, we identified a variant associated with MS in the TNFSF13B gene, which encodes the cytokine BAFF (B-cell-activating-factor). The causal variant is an insertion-deletion, GCTGT>A, where A is the risk allele here in after referred as "BAFF-var". BAFF-var produces a shorter transcript that escapes miR-15 and NF90 inhibition, increasing the production of soluble BAFF and in turn upregulating humoral immunity . Overall, our results dissect the mechanism throught which BAFF-var increases sBAFF production and indicate BAFF as therapeutic target for MS. We decided to use a Virtual Screening approach to identify small molecules able to modulate the interaction of sBAFF with BAFFR. We selected 218 candidate compounds that have been tested in a primary MTT assay. Among them, 8 active compounds have been selected for validation in a secondary assay and 2 compounds showed activity at single concentration.