PROJECT SUMMARY Multiple Sclerosis (MS) is the most common neurological disease of early adulthood and is mediated by autoimmune mechanisms that lead to demyelination and neuronal damage in the central nervous system, resulting in progressive neurological dysfunction. Up to date, there is no cure for the disease and current available treatments focus on preventing future immunological attacks, primarily by suppressing the immune system, and this has adverse side effects that are often severe or fatal. Accordingly, there is a clear unmet need for the development of effective and well-tolerated therapies to arrest MS development. This has been challenging because MS has multiple etiologies (>150 genes identified as risk factors for MS so far) and the molecular mechanisms underlying these etiologies are not well understood. We uncovered the molecular underpinnings of an MS etiology and hope that this knowledge will translate into an accurate therapy for MS. The etiology in question is associated with the interleukin 7 receptor (IL7R) gene, which encodes a cell surface receptor in T cells (hereafter referred to as mIL7R) that plays a central role in the homeostasis of T cells. We previously identified the genetic variant rs6897932 within exon 6 of IL7R to be strongly associated with increased MS risk. Furthermore, we showed that the risk allele of this variant increases exclusion (skipping) of the alternative exon 6 leading to a higher fraction of mRNAs encoding a secreted form of the receptor (sIL7R), leading to elevated levels of circulating sIL7R. This has important repercussions in the development of MS because sIL7R has been shown to aggravate the progression and severity of the disease in the Experimental Autoimmune Encephalomyelitis (EAE) mouse model of MS. Here, we propose to develop a novel biologic MS drug centered on preventing formation of the pathogenic sIL7R. Given that sIL7R is produced by exclusion of exon 6 from IL7R mRNAs, our strategy is to generate splicing-modulating antisense oligonucleotides (ASOs) to correct splicing of IL7R exon 6 and restore expression of IL7R protein isoforms. Our approach represents a major improvement over current MS therapies in that by correcting IL7R splicing, it will diminish expression of the pathogenic sIL7R isoform, without reducing expression of the mIL7R. This is important because mIL7R function is essential for proper immune function and its disruption leads to immunodeficiency. Therefore, our biologic drug, unlike current MS drugs, will not cause immunosuppression. Further supporting a role of IL7R in the development of autoimmunity, this gene has been associated with other autoimmune diseases including Type I Diabetes (T1D), Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE), and most importantly, patients of these diseases have been shown to have elevated levels of circulating sIL7R. Accordingly, the approach proposed here has the potential to yield the first accurate therapy for MS and several autoimmune diseases associated with elevated levels of sIL7R.