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.

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