SBIR-STTR Award

The disorders collectively known as inflammatory bowel disease (IBD) include Crohn's disease (CD) and ulcerative colitis (UC) and affect up to one million people in the US. Both UC and CD result from uncontrolled chronic inflammatory activity in the GI tract. Most current therapeutic agents act by down-regulating chronic inflammation, are not curative and suffer from significant side-effects. In the long-term 40% to 60% of patients do not benefit from the available treatments and thus there is great need for the development of for new therapeutic modalities. Pre-clinical work has demonstrated that immune regulatory mechanisms, specifically the CD4+ CD25+ Foxp3+ cells may play an important role in downregulating the inflammatory activity associated with IBD. The recent discovery that retinoic acid (RA) is a critical co-factor for TGFb-mediated induction of T-regulatory cells and the associated finding that adoptive transfer of RA/TGFb-induced T-regulatory cells can ameliorate IBD in murine models provides a new paradigm for IBD therapy. In light of these findings, this application will test the efficacy of oral TGF?-1 and RA-encapsulated sustained-release biodegradable microparticles in the treatment of IBD. To this end, in Aim 1 the efficacy of oral, sustained-release TGF?-1 and RA formulations will be evaluated in a prevention of disease development model. Aim 2 will test the efficacy of oral, sustained-release TGF?-1 and RA formulations in treatment of established disease. Local and sustained release of TGF?-1 and RA directly to the disease microenvironment from orally-administered PIN microparticles is expected to provide several advantages, including: a) the ability to directly target the disease microenvironment leading to increased efficacy, b) the requirement for lower doses of therapeutic agents thus reducing the toxic side-effects associated with systemic administration and c) sustained-release, reducing the need for frequent administration.

Public Health Relevance:
Current therapies for inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis fail a considerable percentage of patients due to ineffectiveness or therapy limiting side effects. TherapyX, Inc. is developing a more advanced drug delivery system that targets Transforming Growth Factor? -1 and Retinoic Acid to the site of inflammation in the gut thereby reducing systemic side effects. This therapy has the potential to significantly improve morbidity and quality of life of those suffering with IBD.

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Phase I studies established proof-of-principle for the efficacy of oral sustained-release TGF?1 (TPX-6001) and ATRA (TPX-7001) nanoparticles in the treatment of IBD in a murine adoptive T-cell transfer model. Specifically, a two-week regimen of oral TPX-6001 and TPX-7001 achieved a 50-90 % reduction in the severity of multiple disease indicators in mice with advanced IBD. Importantly, co-administration of ATRA with TGF?1 was essential to achieving maximal therapeutic efficacy and disease amelioration was associated with enhanced T-regulatory cell activity in the colon. Phase II work is designed to further optimize therapy protocol in the pre-clinical murine IBD model, establish scale-up manufacturing process and complete toxicology studies leading up to IND filing. In Aim 1, pre-clinical optimization work is completed. To this end, combination TGF?1 and ATRA dosages are optimized first. This combination is then used to identify the optimal therapeutic regimen, determine the ability of treatment to maintain disease remission in the long-term and monitor side-effects. In Aim 2, scale-up process parameters are established to achieve bulk drug production. Batch-to-batch uniformity and shelf-life are determined for the scaled-up product. Aim 3 studies are designed to complete toxicokinetics in 2 mammalian species. These studies are performed in collaboration with the Navigators Toxicology Group at Charles River Laboratories. The data obtained in Aims 1-3 are then utilized in the preparation of an Investigational New Drug (IND) application to the FDA (Aim 4). Successful completion of Phase II studies will facilitate the advancement of TPX-6001/7001 to a Phase I clinical trial in IBD patients.

Public Health Relevance:
Current therapies for inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis fail a considerable percentage of patients due to ineffectiveness or therapy limiting side effects. TherapyX, Inc. is developing a more advanced drug delivery system that targets Transforming Growth Factor ?-1 and Retinoic Acid to the site of inflammation in the gut thereby reducing systemic side effects. This therapy has the potential to significantly improve morbidity and quality of life of those suffering with IBD.

Thesaurus Terms:
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