Our goal is to develop VTC-L35 as a novel tolerance-inducing probiotic platform for the treatment of asthma. According to the CDC, more than 25 million people in America suffer from asthma. Globally, nearly 350 million people suffer from asthma, with more than 300,000 annual deaths attributed to the disease (CDC). Because asthma is fundamentally a disease of immune dysregulation, many current asthma treatments are immunosuppressive agents, including steroids. While these are effective at managing asthma symptoms for many patients, the effects are temporary, have considerable side-effects, and require constant administration. Asthma "attacks" are triggered by a variety of environmental stimuli, the most common of which are aeroallergens. Desensitization protocols exist but are intensive and impractical given the fact that most asthmatics have multiple, often unidentified, allergens. As a result, new therapies are desperately needed to tolerize asthmatics against their own "personalized" allergens. Recently, our project team developed a novel Lactococcus lactis (L. lactis) research strain expressing IL-35 (VTC-L35)26. Oral administration of VTC-L35 effectively reduced the incidence and disease severity of inflammation in both prophylactic and treatment protocols in the mouse model of collagen-induced arthritis model (CIA). VTC-L35 induced CCR6+ and CCR6- CD39+ CD4+ Treg cells in CIA mice. Inquiry into their induction revealed that both CCR6+ and CCR6- Foxp3+/or- CD39+ CD4+ T cells act as the source of the IL-10 induced by VTC-L35. We believe that oral administration of VTC-L35 in the presence of an individual's environmental allergens will induce antigen-specific regulatory cells and restore tolerance to an individual's allergens, reversing asthma symptoms. To validate our approach, we plan to demonstrate that oral administration of VTC-L35 in the presence of low amounts of house dust mite (HDM) antigens prevents allergic and airway symptoms in a mouse model. Subsequently, we will develop and validate a genome-integrated clinical strain. The high-level aims of this Fast-track SBIR application are to 1) demonstrate that our VTC-L35 research strain induces tolerance in a mouse HDM allergy model with no detectable short-term toxicity; 2) develop and characterize a VTC-L35 clinical candidate expressing human IL-35 from a genome-integrated operon; and 3) develop non- GLP and GLP preclinical datasets to support VTC-L35 IND approval. Completion of this proposal will establish a novel IL-35-expressing probiotic platform that can be applied to treat asthma, allergies broadly and even an array of autoimmune diseases.
Public Health Relevance Statement: Project Narrative Asthma and autoimmunity are a major health concern worldwide, particularly in western countries, with symptoms ranging from mild irritation to severe reactions, including debilitation or death. This project aims to develop a novel tolerance-inducing probiotic platform for the treatment asthma. Successful completion of this proposal will lead to the first therapy for dust-mite-induced asthma, and a general tolerance platform for rapid development of a broad array of oral-based tolerance therapies.
Project Terms: Oral Administration; Oral Drug Administration; intraoral drug delivery; Allergens; Americas; Antigens; immunogen; Asthma; Bronchial Asthma; Autoimmune Diseases; autoimmune disorder; Autoimmunity; Autoimmune Status; Automobile Driving; driving; Bacteria; Blood Chemical Analysis; Blood Chemical Analyses; blood chemistry; Cells; Cell Body; Centers for Disease Control and Prevention (U.S.); CDC; Centers for Disease Control; Centers for Disease Control and Prevention; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; Chromosomes; Cessation of life; Death; Disease; Disorder; Freeze Drying; Freeze Dryings; Lyophilization; Genome; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Health; Hematology; Human; Modern Man; Hypersensitivity; Allergy; Immune Tolerance; Immunologic Tolerance; immune system tolerance; immune unresponsiveness; immunological paralysis; Immune System Diseases; Immune Diseases; Immune Disorders; Immune Dysfunction; Immune System Disorder; Immune System Dysfunction; Immune System and Related Disorders; Immunodeficiency and Immunosuppression Disorders; Immunologic Diseases; Immunological Diseases; Immunological Dysfunction; Immunological System Dysfunction; Immunosuppressive Agents; Immunosuppressants; immune suppressive agent; immune suppressor; immunosuppressive substance; immunosuppressor; Incidence; Inflammation; Intestines; Intestinal; bowel; House mice; Mus musculus; Mus; Mice; Mice Mammals; Murine; Operon; Patients; Research; Respiratory Signs and Symptoms; airway symptom; pulmonary symptom; respiratory symptom; Steroids; Steroid Compound; Lactococcus lactis; Streptococcus lactis; Regulatory T-Lymphocyte; Treg; regulatory T-cells; CD4 Positive T Lymphocytes; CD4 Cells; CD4 T cells; CD4 helper T cell; CD4 lymphocyte; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; T4 Cells; T4 Lymphocytes; Toxicology; Treatment Protocols; Treatment Regimen; Treatment Schedule; Measures; Interleukin-10; CSIF; CSIF-10; Cytokine Synthesis Inhibitory Factor; IL-10; IL10; IL10A; Interleukin 10 Precursor; Mediating; Dataset; Data Set; Allergic asthma; atopic asthma; extrinsic allergic asthma; Extrinsic asthma; base; Prophylaxis; Prophylactic treatment; Acute; Clinical; Phase; Physiologic; Physiological; Stimulus; Individual; Therapeutic; Immunes; Immune; Event; irritation; Oral; Clinic; Protocol; Protocols documentation; Reaction; Source; Country; disease severity; Severity of illness; Probiotics; Best Practice Analysis; Benchmarking; Colony-forming units; aeroallergens; airborn allergen; airborne allergen; dust mite; pyroglyphid; trafficking; Toxicities; Toxic effect; Histopathology; Pharmacology and Toxicology; novel; memory T lymphocyte; T memory cell; Allergic; Modeling; Genomics; cell bank; Collagen-Induced Arthritis; Collagen Arthritis; House Dust Mites; Housedust Mites; Pyroglyphidae; House Dust Mites Antigens; Dermatophagoides Antigens; preventing; prevent; genome sequencing; CCR6; CKRL3; Chemokine Receptor-Like 3; G Protein-Coupled Receptor 29; GPR29; GPRCY4; STRL22; CCR6 gene; Dose; Symptoms; SBIR; Small Business Innovation Research; Small Business Innovation Research Grant; Immunochemical Immunologic; Immunologic; Immunological; Immunologically; Immunologics; Monitor; developmental; Development; preclinical; pre-clinical; desensitization; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; novel therapeutics; environmental allergen; murine model; mouse model; therapeutic target; asthmatic; FOXP3; Forkhead Box P3; JM2; SCURFIN; FOXP3 gene; entire genome; full genome; whole genome; symptomatic treatment; treat symptom; symptom treatment; clinical candidate; house dust mite allergy; dust mite allergy; side effect; asthma attack; exacerbation in asthma; exacerbation prone asthma; exacerbation prone asthmatic; asthma exacerbation; PK/PD; pharmacokinetics and pharmacodynamics
