Validation of a Novel NF-KB Inhibitor in Murine 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）影响超过100万美国人。直到最近，这些疾病的治疗方法都是非特异性地抑制免疫反应以抑制肠道炎症。对免疫途径的具体理解导致开发TNF阻断剂作为CD和可能的UC的治疗。然而，这种生物干预仅在少数患者中有效，并且与短期和长期毒性相关。因此，在这些使人衰弱的疾病中存在显著的未满足的医疗需求。实验结果的优势突出了转录因子NF-κ B家族在IBD慢性炎症的起始和持续中的重要性。本I期STTR的目的是提供临床前疗效和机制数据，以支持开发用于治疗IBD的新型细胞渗透性NF-κ B抑制肽。申请组织TheraLogics，Inc.的研究者，一直处于NF-κ B研究的前沿，并拥有NF-κ B抑制剂的知识产权。该待开发的抑制剂是由8个赖氨酸蛋白转导结构域（PTD）和IKB激酶（IKK）抑制序列“NF-κ B必需调节剂”（NEMO）结合结构域（NBD）（统称为PTD-NBD）组成的短肽。与其他正在开发用于慢性炎症性疾病的NF-κ B抑制剂相比，PTD-NBD具有以下优点：（i）抑制活化的NF-κ B（慢性炎症的标志），（ii）不抑制基础NF-κ B活性，其可能参与与炎症不同的基本细胞过程，（iii）具有比其药代动力学性质更持久的药效学作用，以及（iv）全身和局部递送的潜力。与匹兹堡大学的合作将研究人员与基础和临床IBD研究的领导小组结合起来，他们拥有在炎症性疾病中提供细胞渗透肽的专业知识和知识产权。本提案中的实验将提供临床前和药效学数据，以支持在后期研究中开发PTD-NBD作为人类IBD的潜在治疗。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。有许多迫切的，未满足的医疗需求，以开发更安全，更有效的治疗这些终身，衰弱的疾病。在本申请中，TheraLogics，Inc.，和匹兹堡大学提出在IBD小鼠模型中测试一种新的治疗方法，该方法可以通过口服给药，通过关闭一种蛋白质NF-κ B来起作用，NF-κ B是一种打开肠道炎症的“总开关”。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，以评估IBD患者的安全性。

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.