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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要伤口愈合延迟或受损是糖尿病的严重并发症，通常会导致下肢截肢到 2050 年，三分之一的美国人将患上糖尿病，高达 34% 的糖尿病患者将患上糖尿病。足部溃疡 (DFU) 一生中的护理标准包括清创、感染控制、维持治疗。尽管采取了这些干预措施，但仍有大量 DFU 失败。每年花费超过 310 亿美元并增加慢性炎症。氧化应激与糖尿病伤口愈合障碍的发病机制有关。设计并测试了一种新的治疗方法，可协同针对炎症和氧化应激新型氧化铈纳米粒子（CNP），具有活性氧（ROS）清除特性，与糖尿病伤口中缺乏的抗炎 microRNA 模拟物 (miR146a) 结合，并抑制重要的是，我们的新型专利缀合物激活了 NF-kappa-B 诱导的促炎反应。 CNP-miR146a 有效地将 miR146a 递送到伤口中，炎症减少，ROS 减少。使用专为皮内注射配制的 CNP-miR146a (CTX-001)，我们证明了对全层伤口一次性施用 CTX-001 完全纠正了伤口愈合障碍每周重复给药，糖尿病小鼠的伤口显着改善 25%。治疗纠正了糖尿病猪的糖尿病伤口愈合障碍，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制剂 (CTX-004)，根据市场研究，它可用于局部给药，作为一种更具吸引力的替代方案。 Ceria Therapeutics 的这一 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来证明其治疗糖尿病小鼠伤口的功效改善伤口愈合时间和质量所需的有效剂量（目标 1.2）。临床前研究比较CTX-004最佳配方和剂量与唯一FDA的疗效批准用于治疗糖尿病足溃疡的凝胶 (Regranex®) 目标 3 将评估细菌负荷是否有任何影响。关于 CTX-004 在糖尿病小鼠伤口愈合中的功效的努力成功完成。该提案中的内容将使 Ceria 能够将 CTX-004 推进 IND 启用研究，提交 IND 申请，并启动首次人体临床试验。