Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease that is the most common neurological disease of young adults, affecting over 450,000 patients in the US and over 3.5 million patients worldwide. MS is a disease of high unmet medical need, currently treatable with one of twelve FDA approved drugs, all of which result in either significant immunosuppression, immune modulation or immune ablation that can lead to serious adverse effects including opportunistic infections such as PML, malignancy, GI disturbance, hepatic changes, possible fetal teratogenicity, injection site reactions and blood dyscrasias. As the pipeline for treating this chronic inflammatory condition has expanded in a search for more robust efficacy, so have the associated concerns surrounding long term safety and tolerance. 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 response. They have furthermore identified a specific bacterial capsular polysaccharide (PSA) from this organism responsible for the protective effect, and shown that oral administration of purified PSA is protective against multiple mouse experimental allergic encephalomyelitis (EAE) models. Our recent studies funded by the Phase I STTR completed dose-ranging efficacy studies, MTD studies and identified a pharmacodynamic marker of PSA effect. Together, the mouse studies suggest that PSA is a robust modulator of the immune regulatory response that may be effective in the treatment of human MS. Our objective for this Phase 2 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 human in vitro efficacy studies that demonstrate the capacity of PSA to convert nave T cells into Treg cells in culture that secrete IL-10 and a variey of anti-inflammatory molecules, to evaluate the effect of PSA on PBMCs taken from patients with MS.
In Specific Aim 2, we will build on published mouse efficacy studies and results from the Phase 1 STTR to evaluate the effect of PSA in second species efficacy studies using a non-human primate model of EAE.
In Specific Aim 3, we will produce cGMP material that will be used in Phase 1 human clinical trials.
These Specific Aims will lay the essential groundwork allowing PSA to move to IND filing and Phase I clinical trial. 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 2 STTR support will advance this revolutionary treatment option for MS to the brink of human clinical trials, and will pave the way for applicatio 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 450,000 patients in the U.S., and over 3.5 million patients worldwide. The disease knows no borders and over the past 50 years has assumed a similar global incidence and frequency profile that continues to expand. The currently approved platform treatments for MS are immunomodulatory and result in modest to moderate effect on clinical relapse rate. Although the older therapies are safe with very few adverse side effects the more recent therapies either approved by the FDA or under consideration for registration do appear to have greater impact on relapse rate but can exhibit potent immune suppression or immune ablation of the immune system, and are increasingly associated with serious adverse events including cardiac arrhythmia, opportunistic infections, and profound long-term lymphopenia. Thus the niche for an effective, easily administered treatment that will allow for the resetting and repopulation of specific regulatory immune compartments without compromising the host immune system is important and necessary. 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 a single capsular polysaccharide molecule (PSA) 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 2 STTR project will enable crucial studies that will give us safety and efficacy information and allow production of necessary amounts of drug needed to begin human clinical trials.
| Ochoa-Repáraz, Javier; Kasper, Lloyd H (2017) The influence of gut-derived CD39 regulatory T cells in CNS demyelinating disease. Transl Res 179:126-138 |
