A Novel Anti-inflammatory and Anti-oxidant Therapy for Treating Non-healing Diabetic Foot Ulcers

项目摘要 伤口愈合延迟或受损是糖尿病的严重并发症，通常导致下肢截肢。 站。到2050年，1/3的美国人将患糖尿病，高达34%的糖尿病患者将患糖尿病。 足部溃疡（DFU）。DFU的护理标准包括清创、感染控制、维持 潮湿的伤口环境和压力卸载。尽管采取了这些干预措施，但大量DFU还是失败了 每年的治疗费用超过310亿美元。慢性炎症和增加 氧化应激与糖尿病伤口愈合障碍的发病机制有关。我们有 设计并测试了一种新的治疗方法，该方法使用 新型氧化铈纳米颗粒（CNP），其具有活性氧（ROS）清除性质， 与抗炎microRNA模拟物（miR 146 a）缀合，所述miR 146 a在糖尿病伤口中缺乏并抑制 NF-κ B诱导的促炎反应的激活。重要的是，我们的新型专利结合物 CNP-miR 146 a有效地将miR 146 a递送到伤口中并减少炎症和ROS。 使用专门配制用于皮内注射的CNP-miR 146 a（CTX-001），我们证明了 CTX-001对全层伤口的一次性给药完全纠正了 在糖尿病小鼠中的伤口得到了显著的25%的改善。每周重复给药- 治疗纠正了糖尿病猪的糖尿病伤口愈合障碍，与非糖尿病猪的愈合相似 伤口 我们随后开发了CNP-mi 146 a作为羟甲基纤维素凝胶制剂（CTX-004）， 其可用于局部给药，作为基于市场研究的更有吸引力的替代方案。的 CeriaTherapeutics公司的这一I期申请的主要目的是优化CTX-004的凝胶制剂 (Aim 1.1），并通过建立最小的 改善伤口愈合时间和质量所需的有效剂量（目标1.2）。在目标2中，我们将执行 临床前研究，以比较CTX-004的最佳制剂和剂量与唯一FDA 批准的凝胶（Regranex®）用于治疗糖尿病足溃疡。目标3将评估细菌负荷是否有任何影响 CTX-004在糖尿病小鼠伤口愈合中的功效。圆满完成了各项工作， 本提案中所述的内容将使Ceria能够推进CTX-004的IND研究，提交IND申请， 并启动首次人体临床试验

PROJECT SUMMARY Delayed or impaired wound healing is a serious complication of diabetes, often leading to lower limb ampu- tations. By 2050, 1 in 3 Americans will develop diabetes, and up to 34% of diabetic patients will develop a diabetic foot ulcer (DFU) in their lifetime. Standard of care for DFUs includes debridement, infection control, maintaining a moist wound environment, and pressure offloading. Despite these interventions, a large number of DFUs fail to heal and are associated with a cost that exceeds $31 billion annually. Chronic inflammation and increased oxidative stress have been implicated in the pathogenesis of the diabetic wound healing impairment. We have designed and tested a new therapeutic that synergistically targets both inflammation and oxidative stress using novel cerium oxide nanoparticles (CNP), which possess reactive oxygen species (ROS) scavenging properties, conjugated with an anti-inflammatory microRNA mimic (miR146a) that is deficient in diabetic wounds and inhibits the activation of NF-kappa-B-induced pro-inflammatory response. Importantly, our novel, patented conjugate CNP-miR146a efficiently delivers miR146a into the wound and reduces inflammation and ROS. Using a CNP-miR146a specifically formulated for intradermal injection (CTX-001), we demonstrated that a one-time administration of CTX-001 to full-thickness wounds fully corrected the wound healing impairment in diabetic mice and elicited a significant 25% improvement in wounds in diabetic pigs. Repeated weekly admin- istration corrected the diabetic wound healing impairment in diabetic pigs, similar to healing in non-diabetic wounds. We have subsequently developed CNP-mi146a as a hydroxymethylcellulose gel formulation (CTX-004), which can be used for topical administration as a more attractive alternative based on market research. The main objective of this Phase I application by Ceria Therapeutics is to optimize the gel formulation of CTX-004 (Aim 1.1) and demonstrate its efficacy in the treatment of diabetic mouse wounds by establishing the minimum effective dose required to improve the time to and quality of wound healing (Aim 1.2). In Aim 2 we will perform a preclinical study to compare the efficacy of the optimal formulation and dose of CTX-004 with the only FDA approved gel (Regranex®) for treating diabetic foot ulcers. Aim 3 will assess if there is any effect of bacterial load on the efficacy of CTX-004 in the healing of diabetic mouse wounds. Successful completion of the efforts de- scribed in this proposal will position Ceria to advance CTX-004 to IND-enabling studies, file an IND application, and initiate a First-in-Human clinical trial.