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: 8502651
• 负责人: ANTHONY BLIKSLAGER
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502651
• 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; public health relevance; 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.

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100万美国人，并且仍然存在显著的未满足的医疗需求。激活NF？？B转录因子是IBD慢性炎症的起始和持续的中心事件。TheraLogics，Inc.，一直站在NF的最前沿？？B研究并持有与新型NF？？相关的知识产权。B抑制剂肽，包括TLX 1423。TLX 1423是一种由8个赖氨酸（8 K）蛋白转导结构域（PTD）和1个I？B激酶（IKK）抑制序列，“NF？B必需调节因子”（NEMO）结合结构域（NBD）。与其他NF？作为B类抑制剂，TLX 1423具有抑制活化NF？B，慢性炎症的标志，但不抑制基础NF？B活性，参与基本细胞过程，因此与毒性相关。在第一阶段，我们在开发TLX 1423作为IBD治疗方法方面取得了重要的里程碑，并将这些发现发表在《免疫学杂志》上。我们证明了TLX 1423转导到细胞和组织中。在体内，TLX 1423抑制LPS激活的NF？B在回肠，但不抑制基础NF？派尔集合淋巴结B。IL-10-/-小鼠经TLX 1423全身给药后，已建立的结肠炎得到改善，NF？固有层中的B激活。在第1阶段，我们还证明了直肠内给予TLX 1423可改善两种实验性IBD模型的肠道炎症。治疗IBD的理想治疗剂是口服给药。然而，由于两个主要原因，药物递送至发炎的肠仍然是一个挑战：1）缺乏可以局部递送并抑制其在肠免疫细胞中的靶标的高效免疫调节剂，以及2）缺乏将这些药剂携带至炎症部位而在胃肠道中降解最小的媒介物。为第二阶段提案而组建的多学科团队已经为这些障碍制定了创新的解决方案。这将是一个重要的进步，以尽量减少毒性，增加患者的依从性，并提高生活质量。为了应对这些挑战，我们开发了适合局部给药TLX 1423的微乳液（ME）给药系统，并通过肠道释放策略将肽靶向胃肠道炎症区域。我们显示了初步数据，与游离的PTD肽相比，油包水（w/o）ME中的PTD肽有效地递送到小鼠的大肠。 PTD肽。TheraLogics已经招募了CMC，监管和临床顾问将该第2阶段计划的结果转化为下一阶段，包括GMP生产，GLP安全性/毒性研究和IND提交。