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Development of UTL-5b for Rheumatoid Arthritis: Mechanism of Action

UTL-5b 治疗类风湿关节炎的开发：作用机制

基本信息

批准号：
7217623
负责人：
Jiajiu Shaw
金额：
$ 10万
依托单位：
UNITECH PHARMACEUTICALS, INC
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-20 至 2007-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7217623
关键词：
Affect American Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Antirheumatic Agents Arthritis Autoimmune Diseases Biological Biological Assay Biological Response Modifiers Blood Bone and Cartilage Funding Carrageenan Class Clinical Collagen Collagen Arthritis Collagen Type II Complex Development Disease Disease Progression Drug Delivery Systems Drug Formulations Edema Erythema Evaluation Experimental Arthritis Experimental Models Functional disorder Gene Targeting Genes Genetic Goals High Pressure Liquid Chromatography Histopathology Hypergammaglobulinemia Inflammation JAK3 gene Joints Laboratory Finding Legal patent MAP Kinase Kinase Kinase Mediating Methods Modeling Mus Numbers Oral Administration Personal Satisfaction Pharmaceutical Preparations Phase Phase I Clinical Trials Polymerase Chain Reaction Protein Tyrosine Kinase Protocols documentation Rheumatoid Arthritis Score Sepsis Series Severities Small Business Funding Mechanisms Small Business Innovation Research Grant Spleen Spondylitis Survival Rate Synovitis TNF gene Techniques Testing Therapeutic Therapeutic Effect Time Tumor Necrosis Factor-alpha Tumor Necrosis Factors Width arthropathies design human TNF protein improved in vivo indexing inhibitor/antagonist innovation lymph nodes mouse model prophylactic response small molecule

项目摘要

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is one of the most common forms of arthritis, a potentially crippling autoimmune disease that affects more than two million Americans. At the present time, DMARD (Disease Modifying Anti- Rheumatic Drug) is an improved class of arthritis drugs over NSAID (Non-Steroidal Anti-Inflammatory Drug). We have synthesized and screened a series of innovative compounds, UTL series, as potential DMARDs. Among them, UTL-5b is the most promising compound for RA. UTL-5b was shown to significantly lower the elevated blood level of TNF-a and increase the survival rate in an LD100 sepsis animal model. In order to develop more information concerning the potential for UTL-5b to exert anti-arthritic effects, we propose to examine the therapeutic effects of UTL-5b in a CIA mouse model. Specific aims of this Phase I study are: (1) To synthesize 5 g of UTL-5b; (2) To develop, analyze, and optimize a formulation suitable for the proposed in vivo study; (3) To evaluate the anti-arthritic activity of UTL- 5b in the collagen-induced experimental arthritis model. Type II collagen-induced arthritis (CIA) in mice is an experimental model of arthritis with a number of pathological, immunological and genetic features in common with rheumatoid arthritis. A progressive, inflammatory arthritis develops in the majority of immunized animals, which is characterized clinically by erythema and edema, with affected paw width increases of typically 100%. A clinical scoring index has been developed to assess disease progression to joint distortion and spondylitis, and histopathology of affected joints reveals synovitis, pannus formation, and cartilage and bone erosion, which is represented by a validated index. Immunological laboratory findings include high antibody levels to type II collagen, and hyper- gammaglobulinemia. This model has been well established for testing of both biological and pharmacological agents for the treatment of rheumatoid arthritis. Both prophylactic and therapeutic administration of UTL-5b will be investigated in this study. In addition to an evaluation of the influence of UTL-5b on the pathological and immunological aspects of CIA, real-time PCR techniques will be used to examine the gene activity of LPS- induced TNF alpha factor (LITAF), mitogen activated protein kinase kinase kinase 2 (Map3k2), and JAK3 tyrosine-protein kinase (JAK3) in arthritic paws, lymph nodes and spleens In addition to the preliminary MOA study, which indicated that UTL-5b suppresses Map3K2, Jak3, and LITAF, the results from the proposed Phase I studies will be very useful in SBIR Phase II in designing further study protocols to clearly identify the detailed MOA of UTL-5b. This ultimate goal of the current proposal is to develop a small molecule TNF-a modulator as a significantly improved DMARD (disease modifying anti-arthritic drug). This phase 1 study will focus on a comprehensive collagen-induced arthritis animal study.

描述（由申请人提供）：类风湿性关节炎（RA）是一种最常见的关节炎形式，是一种潜在的致残性自身免疫性疾病，影响着超过200万美国人。目前，DMARD（疾病修饰抗风湿药）是一种比NSAID（非甾体抗炎药）改进的一类关节炎药物。我们已经合成并筛选了一系列创新化合物，UTL系列，作为潜在的dmard。其中，UTL-5b是最有希望治疗RA的化合物。在LD100脓毒症动物模型中，UTL-5b可显著降低血液中升高的TNF-a水平，提高存活率。为了进一步了解UTL-5b发挥抗关节炎作用的潜力，我们建议在CIA小鼠模型中检测UTL-5b的治疗作用。本I期研究的具体目的是：(1)合成5 g的UTL-5b；(2)开发、分析和优化适合拟建体内研究的制剂；(3)评价UTL- 5b在胶原诱导的实验性关节炎模型中的抗关节炎活性。小鼠II型胶原诱导关节炎（CIA）是一种实验性关节炎模型，具有许多与类风湿关节炎相同的病理、免疫和遗传特征。在大多数免疫动物中发展为进行性炎性关节炎，其临床特征为红斑和水肿，受影响的爪宽通常增加100%。一个临床评分指标已经被开发出来评估疾病进展到关节扭曲和脊柱炎，受影响关节的组织病理学显示滑膜炎、鞘膜形成、软骨和骨侵蚀，这是一个有效的指数。免疫实验室结果包括II型胶原蛋白抗体水平高，高γ球蛋白血症。这个模型已经很好地建立了用于治疗类风湿性关节炎的生物和药理学试剂的测试。本研究将探讨UTL-5b的预防和治疗作用。除了评估UTL-5b对CIA病理和免疫学方面的影响外，real- real- PCR技术将用于检测LPS诱导的TNF - α因子（LITAF）、丝裂原活化蛋白激酶激酶2 （Map3k2）和JAK3酪氨酸蛋白激酶（JAK3）在关节炎爪子、淋巴结和脾脏中的基因活性。初步MOA研究表明，UTL-5b抑制Map3k2、JAK3和LITAF。拟议的第一阶段研究的结果将对SBIR第二阶段设计进一步的研究方案非常有用，以清楚地确定UTL-5b的详细MOA。当前提案的最终目标是开发一种小分子TNF-a调节剂，作为一种显著改善的DMARD（疾病修饰抗关节炎药物）。该1期研究将集中于一项全面的胶原诱导关节炎动物研究。