Validation of a Novel NF-KB Inhibitor in Murine IBD

新型 NF-KB 抑制剂在小鼠 IBD 中的验证

• 批准号: 7053160
• 负责人: SCOTT E PLEVY
• 金额: $ 21.7万
• 依托单位: THERALOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7053160
• 关键词: Crohn' s disease; I kappa B beta; T cell receptor; antiinflammatory agents; binding proteins; disease /disorder model; drug screening /evaluation; enzyme activity; gastrointestinal disorder chemotherapy; gastrointestinal pharmacology; gene expression; helper T lymphocyte; histopathology; inflammatory bowel diseases; interleukin 10; intestinal mucosa; intraperitoneal injections; kinase inhibitor; laboratory mouse; lysine; myeloperoxidase; nonhuman therapy evaluation; nuclear factor kappa beta; oral administration; peptide analog; ulcerative colitis

DESCRIPTION (provided by applicant): The human inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis (UC), affect over 1 million Americans. Until recently, therapies for these disorders have non-specifically suppressed the immune response to inhibit intestinal inflammation. Specific understanding of immune pathways has led to the development of TNF blockade as a treatment for CD and possibly UC. However, this biological intervention is only effective in a minority of patients, and is associated with short and long term toxicities. Therefore, significant unmet medical needs exist in these debilitating human diseases. A preponderance of experimental results highlights the importance of the NF-KB family of transcription factors in the initiation and perpetuation of chronic inflammation in IBD. The purpose of this Phase I STTR is to provide preclinical efficacy and mechanistic data to support the development of a novel cell permeable NF-KB inhibitory peptide for the treatment of IBD. Investigators at the applicant organization, TheraLogics, Inc., have been at the forefront of NF-KB research and hold an intellectual property position on the NF-KB inhibitor. This inhibitor to be developed is a short peptide comprised of an 8 lysine protein transduction domain (PTD) with an IKB kinase (IKK) inhibitory sequence, "NF-KB essential modulator" (NEMO) binding domain (NBD) (collectively referred to as PTD-NBD). Compared to other NF-KB inhibitors in development for chronic inflammatory diseases, PTD-NBD has the advantages of: (i) inhibiting activated NF-KB, a hallmark of chronic inflammation, (ii) not inhibiting basal NF-KB activity which may be involved in fundamental cellular processes distinct from inflammation, (iii) having pharmacodynamic effects which outlast its pharmacokinetic properties, and (iv) the potential for systemic and local delivery. The collaboration with the University of Pittsburgh combines investigators with expertise in and intellectual property for the delivery of cell permeable peptides in inflammatory diseases with a leading group in basic and clinical IBD research. Experiments in this proposal will provide the preclinical and pharmacodynamic data to support the development of PTD-NBD in later phase studies as a potential therapy for human IBD. Relevance of this research to public health: The human IBDs, CD and UC, affect over 1 million Americans. There are many pressing, unmet medical needs to develop safer and more effective treatments for these lifelong, debilitating illnesses. In this application, investigators at TheraLogics, Inc., and the University of Pittsburgh propose to test a new treatment in mouse models of IBD that can potentially be administered by mouth and works by turning off a protein, NF-KB, which is a "master switch" that turns on inflammation in the intestine. If these studies are successful, future studies will be designed to assess the safety of this new compound, and rapidly develop this treatment to evaluate in people with IBD.

描述(申请人提供)：人类炎症性肠病(IBD)、克罗恩病(CD)和溃疡性结肠炎(UC)影响着100多万美国人。直到最近，针对这些疾病的治疗方法都非特异性地抑制免疫反应，以抑制肠道炎症。对免疫通路的特定理解导致了肿瘤坏死因子阻断作为CD和可能的UC的治疗方法的发展。然而，这种生物干预只对少数患者有效，并与短期和长期毒性有关。因此，在这些令人衰弱的人类疾病中，存在着大量未得到满足的医疗需求。大量的实验结果强调了核因子-KB转录因子家族在IBD慢性炎症的启动和持续过程中的重要性。这项第一阶段研究的目的是提供临床前的疗效和机制数据，以支持开发一种新的细胞通透性的核因子-KB抑制肽用于治疗IBD。申请组织TheraLogics，Inc.的研究人员一直处于核因子-KB研究的前沿，并在核因子-KB抑制剂方面拥有知识产权地位。该抑制剂是一种由8-赖氨酸蛋白转导结构域(PTD)和IKB激酶(IKK)抑制序列组成的短肽，即“NEMO”结合域(NBD)(统称为PTD-NBD)。与其他用于治疗慢性炎症性疾病的核因子-KB抑制剂相比，PTD-NBD具有以下优点：(I)抑制慢性炎症的标志--激活的核因子-kB，(Ii)不抑制基础的核因子-kB活性，它可能参与有别于炎症的基本细胞过程，(Iii)药效学效应超过其药代动力学特性，以及(Iv)全身和局部给药的可能性。与匹兹堡大学的合作将在炎症性疾病中提供细胞透性多肽方面具有专业知识和知识产权的研究人员与基础和临床IBD研究的领导小组结合在一起。该方案中的实验将提供临床前和药效学数据，以支持PTD-NBD作为人类IBD潜在治疗方法的后期研究。这项研究与公共卫生的相关性：人类IBD，CD和UC，影响了100多万美国人。有许多迫切的、尚未得到满足的医疗需求，需要为这些终生的、令人衰弱的疾病开发更安全、更有效的治疗方法。在这项申请中，TheraLogics公司和匹兹堡大学的研究人员提议在IBD的小鼠模型上测试一种新的治疗方法，这种方法可能通过口服给药，并通过关闭一种名为核因子-KB的蛋白质来发挥作用，核因子-KB是开启肠道炎症的“主开关”。如果这些研究成功，未来的研究将被设计来评估这种新化合物的安全性，并迅速开发这种治疗方法来评估IBD患者。