Delivery of Nanoencapsulated TGFbeta and ATRA for the Treatment of IBD

描述(由申请人提供)：第一阶段研究在小鼠过继T细胞转移模型中口服缓释转化生长因子-1(TPX-6001)和全反式维甲酸(TPX-7001)纳米颗粒治疗IBD的有效性的既定原则证明。具体地说，口服TPX-6001和TPX-7001的两周方案在患有晚期IBD的小鼠的多种疾病指标的严重程度上降低了50%-90%。重要的是，联合应用全反式维甲酸和转化生长因子-1是获得最大疗效的关键，疾病的改善与结肠中T调节细胞活性的增强有关。第二阶段的工作旨在进一步优化临床前小鼠IBD模型的治疗方案，建立扩大制造工艺，并完成导致IND申报的毒理学研究。在目标1中，完成了临床前优化工作。为此，首先优化了转化生长因子-1和全反式维甲酸的组合剂量。然后，这种组合被用于确定最佳治疗方案，确定长期维持疾病缓解的治疗能力，并监测副作用。在目标2中，确定了实现大批量药物生产的放大工艺参数。确定放大产品的批次间一致性和保质期。目的3项研究旨在完成2种哺乳动物的毒代动力学。这些研究是与Charles River实验室的导航员毒理学小组合作进行的。在AIMS 1-3中获得的数据随后被用于准备向FDA提交的新药研究(IND)申请(AIM 4)。第二阶段研究的成功完成将促进TPX-6001/7001在IBD患者中进入第一阶段临床试验。 公共卫生相关性：目前治疗炎症性肠病(IBD)的方法，如克罗恩病和溃疡性结肠炎，相当大比例的患者由于无效或治疗限制副作用而失败。TreatyX公司正在开发一种更先进的药物输送系统，该系统针对肠道炎症部位的转化生长因子-1和维甲酸，从而减少全身副作用。这种疗法有可能显著改善IBD患者的发病率和生活质量。

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.