Phase I Amount
$1,021,316
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.
Public Health Relevance Statement: Project Narrative Type 1 Diabetes (T1D) is an autoimmune disease caused by autoreactive T-cell-mediated destruction of islet ß cells. This project aims to develop a novel immunologically-directed L. lactis probiotic bacteria programmed to express and deliver colonization factor antigen I (CFA/I) to induce a bystander tolerance for the treatment of T1D. Successful commercialization would ultimately provide a profound front-line medical advancement for the treatment of T1D.
Project Terms: Nonobese Diabetic Mouse; non-obese diabetic (NOD) mice; nonobese diabetic (NOD) mice; Treatment outcome; Lactococcus; Mediating; base; Chronic; Clinical; Residual state; Residual; Phase; Medical; I-antigen; Ensure; Blood Serum; Serum; drug use; Drug usage; Therapeutic; Genetic; Inflammatory; Life; Emotional well being; Feels well; Normal mental condition; Normal mental state; Normal psyche; Psychological Well Being; Sense of well-being; emotional wellbeing; emotional wellness; mental well-being; mental wellbeing; mental wellness; psychological wellbeing; psychological wellness; self wellness; sense of wellbeing; Well in self; Immunes; Immune; Oral; Clinic; cell type; vision loss; visual loss; Blindness; Probiotics; meetings; Receptor Protein; receptor; Immunomodulation; immune modulation; immune regulation; immunologic reactivity control; immunomodulatory; immunoregulatory; immunoregulation; novel; social; Position; Positioning Attribute; Drug Exposure; Gut Epithelium; gastrointestinal epithelium; Documentation; drug mechanism; Pathogenicity; Insulin Cell; Insulin Secreting Cell; ß-cell; ß-cells; ßCell; Beta Cell; Dose; Consent; Data; in vivo; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Local Therapy; Localized Therapy; Immunologics; Immunochemical Immunologic; Immunologic; Immunological; Immunologically; Monitor; Process; pre-clinical; preclinical; microbiome; autoreactive T cell; self-reactive T cell; commensal microbes; commensal flora; commensal microbiota; commensal microflora; cost; design; designing; novel strategies; new approaches; novel approaches; novel strategy; glycemic control; islet; targeted delivery; site targeted delivery; pathogen; Prevalence; commercialization; Biological Markers; bio-markers; biologic marker; biomarker; insulin dependent diabetes mellitus onset; type 1 diabetes onset; product development; gut microbiota; GI microbiota; Gastrointestinal microbiota; enteric microbial community; enteric microbiota; gastrointestinal microbial flora; gut commensal; gut community; gut flora; gut microbe community; gut microbial community; gut microbial composition; gut microbial consortia; gut microbiotic; gut microflora; intestinal flora; intestinal microbes; intestinal microbiota; intestinal microflora; intestinal tract microflora; phase 1 study; Phase I Study; targeted treatment; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; gut microbiome; GI microbiome; digestive tract microbiome; enteric microbiome; gastrointestinal microbiome; gut-associated microbiome; intestinal biome; intestinal microbiome; Formulation; curative treatments; curative intervention; curative therapeutic; curative therapy; experimental study; experiment; experimental research; first-in-human; first in man; fecal microbiome; stool microbiome; stool-associated microbiome; Intestinal permeability; Gut Epithelial Permeability; Gut Hyperpermeability; Gut permeability; Intestinal Epithelial Permeability; Intestinal Hyperpermeability; Infrastructure; side effect; effector T cell; Teff cell; autoimmune pathogenesis; autoimmune attack; autoimmune destruction; Affect; Antigens; immunogen; Autoimmune Diseases; autoimmune condition; autoimmune disorder; Bacteria; Biological Response Modifier Therapy; Biological Therapy; biological therapeutic; biological treatment; biologically based therapeutics; biotherapeutics; biotherapy; Blood; Blood Reticuloendothelial System; Cell physiology; Cell Function; Cell Process; Cellular Function; Cellular Physiology; Cellular Process; Subcellular Process; Cells; Cell Body; Clinical Research; Clinical Study; Clinical Trials; Dendritic Cells; Veiled Cells; Diabetes Mellitus; diabetes; Insulin-Dependent Diabetes Mellitus; Brittle Diabetes Mellitus; IDDM; Juvenile-Onset Diabetes Mellitus; Ketosis-Prone Diabetes Mellitus; Sudden-Onset Diabetes Mellitus; T1 DM; T1 diabetes; T1D; T1DM; Type 1 Diabetes Mellitus; Type 1 diabetes; Type I Diabetes Mellitus; insulin dependent diabetes; juvenile diabetes; juvenile diabetes mellitus; ketosis prone diabetes; type I diabetes; type one diabetes; Diagnosis; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Environment; Enzyme-Linked Immunosorbent Assay; ELISA; enzyme linked immunoassay; Equilibrium; balance; balance function; Excipients; Feces; stool; Food; Food or Food Product; Goals; Human; Modern Man; Immunity; Incidence; Insulin; Humulin R; Novolin R; Regular Insulin; Intestines; Intestinal; bowel; Ligands; Mucous Membrane; Mucosa; Mucosal Tissue; living system; Organism; Pancreatic beta Cell; Pancreatic ß-Cell; pancreas beta cell; pancreas ß cell; pancreatic b-cell; Structure of beta Cell of islet; Patients; Pharmacokinetics; Drug Kinetics; Pharmacology; Production; QOL; Quality of life; Kidney Insufficiency; Renal Failure; Renal Insufficiency; Kidney Failure; Risk; Running; Safety; Apoplexy; Brain Vascular Accident; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; brain attack; cerebral vascular accident; cerebrovascular accident; Stroke; T-Cells; thymus derived lymphocyte; T-Lymphocyte; Treg; regulatory T-cells; Regulatory T-Lymphocyte; Up-Regulation; Upregulation; Work; colonization factor antigens; cytokine; Measures; Inbred NOD Mice; NOD Mouse; Non-Obese Diabetic Mice
