Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease that is the most common neurological disease of young adults, affecting over 350,000 patients in the US and over 2.5 million patients worldwide. MS is a disease of high unmet medical need, currently treatable with one of several approved drugs, all of which result in either immune modulation or significant immunosuppression or immune ablation that can lead to serious adverse effects including opportunistic infections and malignancy. Symbiotix Biotherapies, Inc. is a startup biotechnology company developing a first-in-class therapeutic agent for MS and other immune- mediated diseases based on discoveries recently emerging from the human microbiome. Our scientific founders have identified a specific gut commensal organism, Bacteroides fragilis, that induces IL-10-secreting regulatory T cells (Treg) that are able to dampen the pro-inflammatory activities of Th1, Th2 and Th17 subsets of T cells. They have furthermore identified a specific bacterial capsular polysaccharide (PSA) from this organism responsible for the protective effect, shown that PSA works through a novel mechanism of Treg activation to expand T cell populations in both germ-free and conventional mice, and shown that oral administration of purified PSA is protective against multiple mouse colitis and experimental allergic encephalomyelitis (EAE) models. Our objective for this Phase 1 STTR project is to conduct key translational studies that will be essential for advancing PSA towards an IND filing as a safe and efficacious new oral treatment for MS. The project consists of 3 Specific Aims:
In Specific Aim 1, we will expand on initial in vivo efficacy studies of oral PSA in the murine EAE model to evaluate the effect of PSA in dose-escalating efficacy studies in two strains of mice induced for EAE.
In Specific Aim 2, we will develop a pharmacodynamic readout of PSA's effect in mouse plasma, PBMC and lymphoid tissue that will be used as a biomarker for preclinical and clinical studies, and also develop an anti-PSA monoclonal antibody that will be used to directly measure PSA in plasma, urine and stool.
In Specific Aim 3, we will evaluate the potential toxicity of PSA using mouse maximal tolerated dose (MTD) studies. Successful completion of this Phase 1 STTR project will generate the preclinical efficacy data, safety data and bioanalytical tools necessary to justify a rapid push towards IND filing that will take PSA into human clinical trials with the support of follow-on Phase II STTR funding. As our company works to translate the groundbreaking academic studies that have resulted in the first therapeutic molecule to emerge from the human microbiome, Phase 1 STTR support will not only lay the groundwork for the development of a revolutionary treatment option for MS, but will also pave the way for application of PSA to other immune-mediated diseases such as inflammatory bowel disease, asthma and rheumatoid arthritis.
Multiple sclerosis (MS) is chronic and severely debilitating immune-mediated inflammatory disease of the human central nervous system, affecting 350,000 patients in the U.S., and over 2.5 million patients worldwide. The currently approved platform treatments for MS are immunomodulatory (glatiramer acetate and interferon- beta) and result in a modest effect on clinical relapse rate but are safe with very few adverse side effects. More recent therapies either approved by the FDA or under consideration for registration appear to have greater impact on relapse rate but can exhibit potent immune suppression (fingolimod, natalizumab) or immune ablation (rituximab, ocrilizumab, alemtuzumab) of the immune system, and are increasingly associated with serious adverse events including cardiac arrhythmia, opportunistic infections such as PML, and profound long- term lymphopenia. Recent work emerging from the human microbiome, which is the collection of >10,000 microbial species that live on and in the human body, has identified a specific bacterial species that resides in the human gut as crucial to maintaining a healthy immune system and protecting against immune-mediated diseases such as MS. The scientific founders of our company have closely studied this microbe, Bacteroides fragilis, and have identified the single molecule that is responsible for the protective effect. Symbiotix Biotherapies, Inc. is a startup biotechnology company formed to bring this new therapy to patients as an orally administered, safe and effective treatment for MS, and the Phase 1 STTR project will enable crucial studies that will give us safety and efficacy information needed to take this therapy into human clinical trials.
