Delivery of Nanoencapsulated TGFbeta and ATRA for the Treatment of IBD

描述（由申请人提供）：统称为炎症性肠病（IBD）的疾病包括克罗恩病（CD）和溃疡性结肠炎（UC），在美国影响多达100万人。UC和CD均由胃肠道中不受控制的慢性炎症活动引起。大多数目前的治疗剂通过下调慢性炎症起作用，不是治愈性的并且具有显著的副作用。从长远来看，40%至60%的患者无法从现有治疗中获益，因此非常需要开发新的治疗方式。临床前工作已经证明，免疫调节机制，特别是CD 4 + CD 25 + Foxp 3+细胞可能在下调IBD相关的炎症活动中发挥重要作用。最近发现视黄酸（RA）是TGF β介导的T调节细胞诱导的关键辅因子，并且相关发现RA/TGF β诱导的T调节细胞的过继转移可以改善小鼠模型中的IBD，这为IBD治疗提供了新的范例。根据这些发现，本申请将测试口服TGF？1和RA包封的缓释可生物降解微粒在IBD治疗中的应用。为此，在目标1中，研究了口服缓释TGF？1和RA制剂将在预防疾病发展模型中进行评估。目的2将测试口服缓释TGF？-β的疗效。1和RA制剂在治疗已确立的疾病中的应用。局部和持续释放TGF？- 1和RA从口服给药的PIN微粒直接靶向疾病微环境预期提供几个优点，包括：a）直接靶向疾病微环境的能力，导致增加的功效，B）需要较低剂量的治疗剂，从而减少与全身给药相关的毒副作用，和c）持续释放，减少频繁给药的需要。公共卫生相关性：目前用于炎症性肠病（IBD）如克罗恩病和溃疡性结肠炎的治疗由于无效或治疗限制性副作用而使相当大比例的患者失败。TherapyX公司正在开发一种更先进的针对转化生长因子的药物输送系统？-1和视黄酸的肠道炎症部位，从而减少全身副作用。这种疗法有可能显着改善IBD患者的发病率和生活质量。

DESCRIPTION (provided by applicant): 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.