Delivery of Nanoencapsulated TGFbeta and ATRA for the Treatment of IBD

描述（由申请人提供）：I期研究建立了口服缓释TGF？1 （TPX-6001）和ATRA （TPX-7001）纳米颗粒在小鼠过继性t细胞转移模型中治疗IBD的作用具体来说，两周的口服TPX-6001和TPX-7001治疗方案使晚期IBD小鼠的多种疾病指标的严重程度降低了50- 90%。重要的是，ATRA与TGF？1对于获得最大的治疗效果至关重要，疾病的改善与结肠中t调节细胞活性的增强有关。II期工作旨在进一步优化临床前小鼠IBD模型的治疗方案，建立规模化生产工艺，完成毒理学研究，为IND申请做准备。Aim 1完成临床前优化工作。为此，联合TGF？首先优化1和ATRA剂量。然后使用这种组合来确定最佳治疗方案，确定治疗长期维持疾病缓解的能力并监测副作用。在目标2中，建立放大工艺参数以实现原料药生产。批量到批量的均匀性和保质期被确定为放大产品。目的3研究旨在完成2种哺乳动物的毒性动力学。这些研究是与查尔斯河实验室的航海家毒理学小组合作进行的。在Aims 1-3中获得的数据然后用于准备向FDA提交的研究性新药（IND）申请（Aim 4）。成功完成II期研究将促进TPX-6001/7001进入IBD患者的I期临床试验。

DESCRIPTION (provided by applicant): 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.