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

一种治疗不愈合糖尿病足溃疡的新型抗炎和抗氧化疗法

• 批准号: 10600900
• 负责人: David Jackson
• 金额: $ 29.92万
• 依托单位: CERIA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600900
• 关键词: 16S ribosomal RNA sequencing; Affect; American; Amputation; Anti-Inflammatory Agents; Antibiotic Therapy; Area; Bacterial Infections; Becaplermin; Chronic; Clinical; Clinical Trials; Complications of Diabetes Mellitus; Control Groups; Cyclophosphamide; Data; Debridement; Diabetes Mellitus; Diabetic Foot Ulcer; Diabetic mouse; Diffusion; Disease; Dose; Exhibits; FDA approved; Family suidae; Fluorescein-5-isothiocyanate; Fluorescence Microscopy; Formulation; Gel; Goals; Human; Image; Impaired wound healing; Infection Control; Inflammation; Inflammatory Response; Intervention; Legal patent; Limb structure; Literature; Lower Extremity; Market Research; Measures; Methods; MicroRNAs; Modeling; Mus; NF-kappa B; Oxidants; Oxidative Stress; Pathogenesis; Patients; Peptides; Pharmacotherapy; Phase; Phase III Clinical Trials; Platelet-Derived Growth Factor; Population; Positioning Attribute; Property; Reactive Oxygen Species; Recombinants; Reporting; Research; Salvelinus; Small Business Innovation Research Grant; Suspensions; Testing; Therapeutic; Thick; Time; Topical application; Ulcer; Wound Infection; Wound models; antioxidant therapy; base; cerium oxide nanoparticle; common treatment; comparative efficacy; cost; design; diabetic; diabetic patient; diabetic ulcer; diabetic wound healing; effective therapy; efficacy study; first-in-human; healing; improved; intradermal injection; male; meetings; microbiome; mimetics; non-diabetic; non-healing wounds; novel; novel therapeutics; preclinical development; preclinical efficacy; preclinical study; pressure; side effect; standard of care; wound; wound closure; wound environment; wound healing

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.

项目总结 伤口愈合延迟或受损是糖尿病的一种严重并发症，通常会导致下肢闭锁。 注解。到2050年，三分之一的美国人会患上糖尿病，高达34%的糖尿病患者会患上糖尿病 足部溃疡(DFU)在他们的一生。DFU的护理标准包括清创、感染控制、维护 湿润的伤口环境，压力卸载。尽管有这些干预措施，大量的DFU还是失败了 治愈并与每年超过310亿美元的成本相关。慢性炎症和加重 氧化应激参与了糖尿病创面愈合障碍的发病机制。我们有 设计并测试了一种新的疗法，协同针对炎症和氧化应激 新型氧化铈纳米颗粒(CNP)，具有清除活性氧物种(ROS)的性能， 与糖尿病创面缺乏的抗炎microRNA模拟物(MiR146a)结合并抑制 活化核因子-kappaB诱导的促炎反应。重要的是，我们的新奇专利共轭 CNP-miR146a有效地将miR146a送入伤口，减少炎症和ROS。 使用专门用于皮内注射的CNP-miR146a(CTX-001)，我们证明了a 全层创面一次性应用CTX-001可完全纠正创面愈合障碍。 并使糖尿病小鼠的伤口明显改善25%。每周重复管理- 治疗纠正了糖尿病猪的糖尿病创面愈合障碍，类似于非糖尿病猪的愈合 伤口。 我们随后开发了CNP-mi146a作为羟甲基纤维素凝胶配方(CTX-004)， 它可以作为基于市场研究的更具吸引力的替代方案用于局部给药。这个 Ceria治疗公司这一I期应用的主要目标是优化CTX-004的凝胶配方 (目标1.1)，并通过建立最低限度的 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，我们将执行一项 CTX-004最佳处方和剂量与单用FDA疗效比较的临床前研究 批准的凝胶(Regranex®)用于治疗糖尿病足部溃疡。目标3将评估细菌负荷是否有任何影响 CTX-004对糖尿病小鼠创面愈合作用的研究圆满完成排查工作 这份建议书中描述的将使CEIA将CTX-004推进到IND使能研究，提交IND申请， 并启动首个人类临床试验。