Rise Therapeutics, LLC SBIR Phase II Award, July 2022

Project Summary Our goal is to develop a novel, immunologically-directed L. lactis probiotic-based therapeutic for the treatment of Type 1 Diabetes (T1D)1. T1D is a devastating disease and there is no curative treatment, with insulin the only drug available. T1D affects not only glycemic control but also many important aspects of a patient's life, including emotional well-being, quality of life, working ability, and social interactions25. In addition, T1D patients present increased risk of developing blindness, kidney failure, stroke, and additional autoimmune disorders. Therefore, there is an urgent need to develop new cutting-edge strategies for T1D. The steep rise in the incidence and prevalence of T1D cannot be explained solely by genetic factors implicating the environment, and specifically the gut microbiome, as culprit for the disease etiopathogenesis62. The gut microbiome influences multiple host functions, including immunity, and T1D patients present changes in gut microbiota associated with immunological deregulation and gut leakiness6. Moreover, while fecal microbiome therapy (FMT) is fraught with difficulties as a general treatment including possible transfer of pathogenic organisms, controlled clinical studies demonstrate that FMT halts the progress of new onset T1D63. A promising and potentially safe approach to the treatment of T1D that leverages the body’s own natural microbiome-associated immune regulatory mechanisms is to use oral, gut localized and targeted therapy to control specific interactions between commensal microbes and host immune cells lining the gut epithelial layer that express key immunoregulatory receptors. R-2487 is an immunologically-directed 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 T1D by combining the safety of a probiotic with the targeted functionality of the CFA/I ligand. R-2487 has been showed to diminish T1D in animals9. R-2487 works via targeted delivery of CFA/I to the intestinal tract where it engages mucosal dendritic cells to drive systemic upregulation of regulatory T cells (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 T1D, 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 and file an IND with the FDA. The key aims of this proposal are: 1) finalize in vivo characterization of R-2487; 2) GMP manufacturing of drug substance and drug product; and 3) submit IND application to evaluate activity in recent onset T1D patients. Successful commercialization of R-2487 will provide a profound medical advancement for treating T1D.