A Novel IL-35 Expressing Probiotic Platform for Inducing Allergen Specific Tolerance

点击翻译按钮获取中文摘要

Project Summary 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.