529 The effect of a novel inhibitor of Slc7a5 on remyelination in MS

Abstract

Objectives/Goals: This study aims to first understand the expression of the L-type amino acid transporter, Slc7a5, in demyelinated plaques in postmortem multiple sclerosis (MS) CNS tissue. It also seeks to understand the effect of a novel inhibitor of Slc7a5 on remyelination in mice with experimental autoimmune encephalomyelitis. Methods/Study Population: Using single-cell RNA sequencing (scRNA-seq), we will examine the expression of Slc7a5 in demyelinated plaques in postmortem CNS tissue of patients with MS compared to non-lesioned regions (n  =  3/group). Using visually evoked potential (VEP) on mice with experimental autoimmune encephalomyelitis (EAE), we will determine the ability of the Slc7a5 allosteric inhibitor OKY-034 to promote remyelination compared to EAE-only controls (n  =  10/group). Lastly, we will use spatial transcriptomics with scRNA-seq to map transcriptional activity within different populations of cells to determine how OKY-034 changes gene expression in specific cell types compared to EAE-only controls (n  =  3/group). Results/Anticipated Results: A conditional knockout of Slc7a5 showed that microglial activation and oligodendrocyte differentiation were affected in demyelinated lesions. This suggests that it plays a role in numerous cell types in active demyelinated plaques, which is what we expect to find from our scRNA-seq data in post-mortem CNS tissue of patients with MS. Measuring VEP is a noninvasive way to measure remyelination in both clinical and research settings. OKY-034 increases oligodendrocyte differentiation suggesting remyelination, so we expect that administration of OKY-034 in mice with EAE will lead to restored VEP compared to control and EAE-only mice. Lastly, because OKY-034 reduces inflammation, we expect to see a decrease in gene expression for genes involved in an immune response. Discussion/Significance of Impact: Completion of this study will lead to understanding what the effect the allosteric Slc7a5 inhibitor OKY-034 has on remyelination and whether it may serve as a novel therapeutic drug that can be administered orally for the treatment of MS. This could lead to its further development as a treatment for progressive MS.