Delivery of Nanoencapsulated TGFbeta and ATRA for the Treatment of IBD

纳米封装的 TGFbeta 和 ATRA 的递送用于治疗 IBD

• 批准号: 7538712
• 负责人: Thomas F Conway
• 金额: $ 17.25万
• 依托单位: THERAPYX, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-20 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538712
• 关键词: Acute; Adoptive Transfer; Adverse effects; Affect; CD4 Positive T Lymphocytes; Cells; Chronic; Crohn' s disease; Development; Disease; Disease model; Disease remission; Dose; Drug Delivery Systems; Drug Formulations; Encapsulated; Gastrointestinal tract structure; Generations; Goals; IL2RA gene; Immune; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Light; Mediating; Mediator of activation protein; Modality; Modeling; Monitor; Morbidity - disease rate; Mus; Oral; Oral Administration; Patients; Phase; Phase I Clinical Trials; Play; Polymers; Prevention therapy; Production; Public Health; Quality of life; Research; Role; SCID Mice; Score; Severity of illness; Site; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Transforming Growth Factor beta; Transforming Growth Factors; Treatment Efficacy; Tretinoin; Ulcerative Colitis; Week; Weight; Work; base; cytokine; design; disorder prevention; improved; model development; novel therapeutics; peripheral blood; pre-clinical; prevent; reconstitution

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.

描述（由申请人提供）：共同称为炎症性肠病（IBD）的疾病包括克罗恩病（CD）和溃疡性结肠炎（UC），并影响美国多达100万人。 UC和CD均来自胃肠道不受控制的慢性炎症活性。大多数当前的治疗剂通过下调慢性炎症而作用，没有治愈性，并且副作用严重。长期40％至60％的患者无法从可用的治疗中受益，因此非常需要开发新的治疗方法。临床前的工作表明，免疫调节机制，特别是CD4+ CD25+ FOXP3+细胞可能在下调与IBD相关的炎症活性方面起重要作用。最近发现，视黄酸（RA）是TGFB介导的T调节细胞诱导的关键辅助因素，并且相关的发现，即RA/TGFB诱导的T调节细胞的收养转移可以改善鼠模型中IBD的IBD，从而为IBD疗法提供了一种新的IBD治疗范式。鉴于这些发现，该应用将测试口服TGF？-1的功效，并在IBD治疗中囊括了持续释放的可生物降解的微粒。为此，在AIM 1中，将在预防疾病发展模型中评估口服，持续释放的TGF？-1的功效。 AIM 2将测试口服，持续释放的TGF？-1和RA制剂在治疗既定疾病中的疗效。局部和持续释放TGF？-1和RA直接从口腔管理的销钉微粒颗粒中直接释放到疾病微环境中，预计将提供多个优势，包括：a）直接靶向疾病微环境的能力，导致疗效提高，b）降低了与毒性促进的毒性降低毒性的需求，从而降低了毒性的促进性，并降低了氧化的促进性，并降低了促进良好的促进性，并降低了促进良好的促进效率，并降低了促进的促进症状的效果。用于频繁给药。公共卫生相关性：当前针对炎症性肠病（IBD）的疗法（例如克罗恩病和溃疡性结肠炎）由于无效或治疗限制了副作用而导致的患者很大一部分。 Therapyx，Inc。正在开发一个更先进的药物输送系统，该系统针对转化生长因子？ -1和视黄酸到肠道中的炎症部位，从而减少了全身副作用。这种疗法有可能显着改善患有IBD的人的发病率和生活质量。