Validation of a Novel NF-kB Inhibitor in Inflammatory Bowel Disease

新型 NF-kB 抑制剂在炎症性肠病中的验证

• 批准号: 8251611
• 负责人: SCOTT E PLEVY
• 金额: $ 69.81万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251611
• 关键词: Acute; Address; Affect; American; Animals; Apoptosis; Binding; Biological; Biological Assay; Biotechnology; Cell physiology; Cells; Chemicals; Chronic; Clinical; Colitis; Collaborations; Colon; Crohn' s disease; Data; Development; Disease model; Dose; Drug Delivery Systems; Drug Formulations; Enteral; Epithelial; Event; Experimental Models; Family suidae; Feces; Gastrointestinal tract structure; Gelatin; High Pressure Liquid Chromatography; Histologic; Human; Hydrogels; Immune; Immunology; Industry; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intellectual Property; Interleukin-10; Intestines; Journals; Label; Lamina Propria; Large Intestine; Lead; Liquid substance; Lysine; Measures; Medical; Modeling; Mus; NF-kappa B; North Carolina; Oils; Oral; Oral cavity; Particle Size; Peptides; Permeability; Pharmacodynamics; Phase; Phosphotransferases; Principal Investigator; Property; Proteins; Publishing; Quality of life; Reperfusion Injury; Research; Research Personnel; Safety; Schools; Simulate; Site; Small Business Technology Transfer Research; Solutions; Structure of aggregated lymphoid follicle of small intestine; System; Tertiary Protein Structure; Testing; Therapeutic Agents; Thermodynamics; Time; Tissues; Toxic effect; Translating; Ulcerative Colitis; Universities; Validation; Veterinary Medicine; Viscosity; Water; Work; base; capsule; chemokine; comparative; compliance behavior; cytokine; design; ileum; improved; in vivo; inhibitor/antagonist; innovation; medical schools; mouse model; multidisciplinary; mutant; novel; programs; response; transcription factor

DESCRIPTION (provided by applicant): The human inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, affect over one million Americans and significant unmet medical needs still exist. Activation of NF??B transcription factors are central events in the initiation and perpetuation of chronic inflammation in IBD. TheraLogics, Inc., have been at the forefront of NF??B research and hold intellectual property pertaining to novel NF??B inhibitor peptides including TLX1423. TLX1423 is a peptide comprised of a 8 lysine (8K) protein transduction domain (PTD) with an I?B kinase (IKK) inhibitory sequence, "NF??B essential modulator" (NEMO) binding domain (NBD). Compared to other NF??B inhibitors, TLX1423 has the advantages of inhibiting activated NF??B, a hallmark of chronic inflammation, but not inhibiting basal NF??B activity, involved in fundamental cellular processes thus correlating with toxicity. During phase 1, we achieved important milestones in the development of TLX1423 as a therapy for IBD and published these findings in the Journal of Immunology. We demonstrated transduction of TLX1423 into cells and tissues. In-vivo, TLX1423 inhibited LPS-activated NF??B in the ileum, but did not inhibit basal NF??B in Peyer's patches. IL-10-/- mice treated systemically with TLX1423 demonstrated amelioration of established colitis and decreased NF??B activation in the lamina propria. In phase 1, we also demonstrated that intrarectal administration of TLX1423 results in amelioration of intestinal inflammation in two experimental IBD models. The ideal therapeutic agent to treat IBD would be administered by mouth. However, drug delivery to the inflamed intestine remains a challenge for two main reasons: 1) lack of highly effective immunomodulatory agents that can be delivered locally and inhibit their targets in intestinal immune cells and, 2) lack of vehicles to carry these agents to the site of inflammation with minimal degradation in the GI tract. The multidisciplinary team assembled for this phase 2 proposal has developed innovative solutions to these hurdles. This would be an important advancement to minimize toxicity, increase patient compliance, and improve quality of life. To address these challenges, we have developed microemulsion (ME)- based delivery systems suitable for local administration of TLX1423, and via enteric release strategies, target the peptide to inflamed regions of the GI tract. We show preliminary data that PTD peptides in water-in-oil (w/o) MEs are efficiently delivered to the large intestine in mice as compared to free PTD peptides. TheraLogics has enlisted CMC, regulatory and clinical consultants to translate results of this phase 2 program into the next phases, including GMP manufacturing, GLP safety/toxicity studies, and an IND submission. PUBLIC HEALTH RELEVANCE: This is an STTR application representing an industry-academic collaboration between TheraLogics, Inc., the University of North Carolina at Chapel Hill, and the North Carolina State School of Veterinary Medicine. The applicant organization is TheraLogics, Inc., a small North Carolina based biotechnology company. The Principal Investigator on this application is Scott E. Plevy in the University of North Carolina School of Medicine. The purpose of this application is to develop a novel NF??B inhibitor for the treatment of inflammatory bowel disease. The investigators have already been successful in demonstrating efficacy of the NF??B inhibitor in experimental models of colitis. This application will further develop this inhibitor for oral delivery and further test this molecule in small and lrge animals. It is our hope that the work performed in this application will lead to clinical development in humans in the next phase.

描述（由申请人提供）：人类炎症性肠病（IBD），克罗恩病和溃疡性结肠炎，影响超过一百万的美国人，并且仍然存在大量的未满足医疗需求。 NF ?? B转录因子的激活是IBD慢性炎症的启动和延续中的中心事件。 Theralogics，Inc。一直处于NF ?? B研究的最前沿，并拥有与新的NF ?? B ?? B抑制剂肽有关的知识产权。 TLX1423是由8赖氨酸（8K）蛋白转导域（PTD）组成的，具有I？B激酶（IKK）抑制序列，“ NF ?? B ESSECTER调节剂”（NEMO）结合结构域（NBD）。与其他NF ?? B抑制剂相比，TLX1423具有抑制活化的NF ?? B的优势，NF ?? B是慢性炎症的标志，但不抑制基础NF ?? B的活性，与基本细胞过程有关，因此与毒性相关。在第1阶段，我们在TLX1423的发展中取得了重要的里程碑，作为IBD的疗法，并在《免疫学杂志》中发表了这些发现。我们证明了TLX1423转移到细胞和组织中。 Vivo，TLX1423在回肠中抑制了LPS激活的NF ?? B，但并未抑制Peyer斑块中的基础NF ?? B。用TLX1423全身治疗的IL-10 - / - 小鼠表现出既定结肠炎的改善，并减少了固有椎板的NF ?? B激活。在第1阶段，我们还证明了直肠内施用TLX1423在两个实验IBD模型中导致肠炎的改善。治疗IBD的理想治疗剂将由口腔施用。但是，由于两个主要原因：1）缺乏可以在局部输送的高效免疫调节剂并抑制其在肠道免疫细胞中的靶标的高度有效的免疫调节剂的挑战仍然是一个挑战，并且2）缺乏将这些试剂运送到GI Tract中最小降解的炎症部位。为此2阶段提案组成的多学科团队为这些障碍开发了创新的解决方案。这将是最大程度地减少毒性，提高患者依从性并改善生活质量的重要进步。为了应对这些挑战，我们开发了适用于TLX1423的地方给药的基于微乳液（ME）的递送系统，并通过肠释放策略将肽靶向于发炎的GI区域。我们显示初步数据表明，与游离相比 PTD肽。 Theralogics已吸引了CMC，监管和临床顾问，将该2阶段计划的结果转化为下一个阶段，包括GMP制造，GLP安全/毒性研究以及IND提交。 公共卫生相关性：这是一个STTR应用程序，代表Theralogics，Inc。，北卡罗来纳大学教堂山分校和北卡罗来纳州兽医学院之间的行业学术合作。申请人组织是Theralogics，Inc。，这是一家位于北卡罗来纳州的小型生物技术公司。该应用程序的主要研究人员是北卡罗来纳大学医学院的Scott E. Plevy。该应用的目的是开发一种新型的NF ?? B抑制剂来治疗炎症性肠病。研究人员已经成功地证明了NF ?? B抑制剂在结肠炎实验模型中的功效。该应用将进一步开发该抑制剂以进行口服递送，并进一步测试小型和LRGE动物中的该分子。我们希望在此应用程序中执行的工作将导致下一阶段的人类临床发展。