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（由申请人提供）：人类炎症性肠病（IBD），克罗恩病（CD）和溃疡性结肠炎（UC）影响了100万以上的美国人。直到最近，这些疾病的疗法对抑制肠炎的免疫反应非特异性抑制。对免疫途径的具体理解已导致TNF阻滞的发展作为CD和UC的治疗方法。但是，这种生物学干预仅在少数患者中有效，并且与短期和长期毒性有关。因此，这些使人衰弱的人类疾病存在着重要的未满足医疗需求。大量的实验结果凸显了NF-KB转录因子家族在IBD慢性炎症的启动和永续存在中的重要性。 I阶段ISTTR的目的是提供临床前功效和机械数据，以支持新型细胞可渗透的NF-KB抑制性肽的开发，以治疗IBD。申请人组织Theralogics，Inc。的研究人员一直处于NF-KB研究的最前沿，并在NF-KB抑制剂上担任知识产权。这种要开发的抑制剂是由8赖氨酸蛋白转导域（PTD）组成的短肽，该肽具有IKB激酶（IKK）抑制序列，“ NF-KB必需调节剂”（NEMO）结合结构域（NEMO）结合结构域（NBD）（NEMO）结合结构域（NBD）（集体称为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, （iv）全身和本地交付的潜力。与匹兹堡大学的合作结合了研究人​​员与知识产权和知识产权的专业知识，以在炎症性疾病中提供可渗透的肽与基础和临床IBD研究领域的领先小组。该提案中的实验将提供临床前和药效数据，以支持PTD-NBD在后期研究中的发展，作为人IBD的潜在疗法。这项研究与公共卫生的相关性：人类IBD，CD和UC影响超过100万美国人。对于这些终生，使人衰弱的疾病，有许多紧迫，未满足的医疗需要开发更安全，更有效的治疗方法。在此应用程序中，Theralogics，Inc。和匹兹堡大学的研究人员提议在IBD小鼠模型中测试一种新处理，该方法可能通过口腔来管理，并通过关闭蛋白质NF-KB来工作，这是一种“主开关”，这是一种肠道炎症的“主开关”。如果这些研究成功，未来的研究将旨在评估这种新化合物的安全性，并迅速开发这种治疗方法以评估IBD患者。