A Novel Immunological-Directed Synthetic Biology-Based Drug for the Treatment of Multiple Sclerosis

Project Summary Our goal is to develop a novel, immunological-directed synthetic biology-based therapeutic for the treatment of Multiple Sclerosis (MS). MS is a devastating characterized by an exacerbated immune response that destroy myelin. This disease affects many important aspects of a patient's life, including emotional well-being, quality of life, working ability, and social interactions. In addition, MS patients present increased risk of severe secondary complications, including blindness, kidney failure, stroke, and additional autoimmune disorders. Therefore, there is an urgent need to develop new cutting-edge strategies to treat MS. The gut–brain axis has been recognized as a bi-directional communication system connecting the CNS to the gut13 that is now implicated in the disease etiopathogenesis. MS patients present a dysbiotic gut microbiome with a deficiency in regulatory T cells (Tregs)15, 16, 18, 19. Probiotic consumption showed an improvement in the disease severity by increasing anti-inflammatory cytokines and Tregs17, corroborating the important role of the gut-brain axis. A promising approach for the treatment of MS is to leverage the body’s own natural microbiome- associated immune regulatory mechanisms with oral, gut localized and targeted therapy to control host immune cells lining the gut epithelial layer to direct reestablishment of systemic immune homeostasis. R-2487 is an immunologically-directed recombinant probiotic consisting of the food-grade, Lactococcus (L.) lactis strain expressing Colonization Factor Antigen I (CFA/I). R-2487 is a live biotherapeutic product that represents a novel breakthrough approach for the treatment of MS by combining the safety of a probiotic with the targeted functionality of the CFA/I ligand. R-2487 has been showed to diminish MS-like symptoms in animals21, 22. R-2487 works via targeted delivery of CFA/I to the intestinal tract where it engages mucosal dendritic cells to drive systemic upregulation of Tregs. The induction of Tregs resets the balance with proinflammatory T effector cells to reduce inflammatory processes that contribute to autoimmune disease, leading to bystander tolerance. Since heterogeneous pathogenesis of autoimmune disease, including MS, poses many challenges for therapies that target specific antigens for tolerization or a single cell type or cytokine, R-2487-mediated bystander tolerance induction offers a broader and more impactful mechanism of disease correction. This application is designed to complete R-2487 IND enabling studies to support initiation of a first-in-human MS trial for this important new therapy. The key aims of this proposal are: 1) finalize in vivo characterization of R-2487, identifying starting clinical dose and important biomarkers to be used in the clinical trial; 2) manufacture of clinical GMP drug substance and drug product; and 3) complete the IND-enabling GLP toxicology study. Successful commercialization of R-2487 will provide a profound medical advancement for treating MS.