COATs: Collagen-mimetic peptide and therapeutic gene-modified collagens for cell-mediated healing of diabetic foot ulcers

COAT：胶原模拟肽和治疗性基因修饰胶原，用于细胞介导的糖尿病足溃疡愈合

• 批准号: 10629445
• 负责人: Kristi L Kiick
• 金额: $ 54.08万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629445
• 关键词: Amputation; Behavior; Behavior Control; Binding; Biocompatible Materials; Biological Assay; Cells; Cessation of life; Chromosome Mapping; Chronic; Climate; Clinical; Collagen; Collagen Fibril; Collagen Gene; Complement; Complex; Coupled; Cytokine Gene; DNA; DNA Integration; Data; Diabetic Foot Ulcer; Dose; Engineering; Environment; Equilibrium; Etiology; Exudate; Fibroblasts; Friends; Gene Delivery; Gene Expression; Gene Modified; Gene Transfer; Genes; Growth Factor; Growth Factor Gene; Growth Factor Overexpression; Half-Life; Health; Human; IL4 gene; Immunology; Incidence; Inflammatory; Interleukin-10; Investigation; Leg; Link; Macrophage; Mediating; Membrane; Modality; Modeling; Modification; Mus; Outcome; Patient-Focused Outcomes; Peptide Hydrolases; Phenotype; Platelet-Derived Growth Factor; Production; Property; Regenerative Medicine; Research Project Grants; Role; Safety; Signal Transduction; Skin repair; Testing; Therapeutic; Time; Translating; Translations; Variant; acute wound; chronic wound; cost; cytokine; design; diabetic; diabetic ulcer; economic impact; gene product; gene therapy; healing; immunoregulation; improved; in vivo; inflammatory milieu; innovation; insight; mortality risk; peptidomimetics; pre-clinical; regenerative therapy; repaired; scaffold; therapeutic gene; therapeutic protein; wound; wound bed; wound care; wound dressing; wound environment; wound healing; wound treatment

PROJECT SUMMARY – Diabetic foot ulcers (DFU) are an enormously costly worldwide health concern. They cause nearly 80,000 lower leg amputations annually in the U.S. alone and are associated with significantly increased likelihood of death. Strategies to improve their healing have been a subject of intense study for decades, yet myriad cellular and pathophysiological abnormalities continue to severely limit efficacy of standard therapies. Promising therapeutic alternatives include the application of cellular scaffolds, topical growth factors (especially platelet-derived growth factor), or combination wound dressings. However, the incidence of complete closure remains strikingly low and growth factor delivery strategies largely fail owing to their instability in the inflammatory, MMP-rich environment of the chronic wound. New strategies that can normalize this proteolytic and inflammatory environment, by stimulating local production of therapeutic proteins by fibroblasts and macrophages, would thus offer a provocative approach to improve clinical outcomes. We have recently demonstrated that protease activity in the wound bed can be harnessed to stimulate localized growth factor gene delivery and provide tailorable expression of growth factors over multiweek timeframes. We introduce collagen mimetic peptide (CMP) and therapeutic gene-modified collagens (COATs) as a platform for (i) robust retention of growth factor-encoding polyplexes in collagen- containing wound dressings and (ii) localized, cell-initiated gene delivery during collagen remodeling. Because COATs integrate DNA polyplexes directly into collagen fibrils, our approaches have been shown to significantly improve in vivo wound repair at concentrations of growth factors orders of magnitude lower than those in currently employed topical therapies. These outcomes, coupled with recent advances in the translation of other gene therapies, suggests the high potential for clinical impact of the COATs platform. In the proposed R01 program, we will apply COATs in experimental DFUs and cell-based assays to understand three important aspects of orchestrating wound repair, in the following three Aims. In Aim 1, we will probe variations in CMP modifications that optimize the extended delivery of genes (initially for platelet-derived growth factor (PDGF)) in a murine diabetic wound environment. In Aim 2, we will complement these studies with cell-based investigations that elucidate the role of MMPs (soluble and membrane-bound) in regulating PDGF gene delivery by COATs and PDGF protein lifetime. In Aim 3, we will test how COATs-mediated, sequential delivery of genes for immunomodulatory cytokines (IL4 and IL10) modulates MMP activity in DFUs. These approaches will provide both mechanistic insights for resolving the chronicity of DFUs, and also a new platform that could be integrated into existing wound-care strategies to dramatically improve clinical outcomes.

项目摘要 - 糖尿病足溃疡（DFU）是全球范围内昂贵的健康问题。他们 仅在美国，每年造成近80,000个小腿截肢 死亡的可能性增加。改善康复的策略一直是一项深入研究的主题 几十年来，但无数的细胞和病理生理异常仍然严重限制了 标准疗法。有希望的治疗替代方法包括应用细胞支架，局部 生长因子（尤其是血小板衍生的生长因子）或结合伤口敷料。但是， 完全关闭的发生率仍然很低，增长因子输送策略在很大程度上失败了 它们在慢性伤口的炎症，富含MMP的环境中的不稳定性。可以的新策略 通过刺激局部产生治疗蛋白的生产来使这种蛋白水解和炎症环境归一化 因此，通过成纤维细胞和巨噬细胞，将提供一种挑衅性的方法来改善临床结果。 我们最近证明了伤口床中的蛋白酶活动可以利用 刺激局部生长因子基因递送并提供可调节的生长因子的表达 超过多周的时间表。我们引入胶原蛋白模拟肽（CMP）和治疗基因修饰 胶原蛋白（涂层）作为（i）胶原蛋白中生长因子编码多路复管的强大保留 包含伤口敷料和（ii）胶原蛋白重塑期间局部的，细胞引发的基因递送。因为 涂层直接整合到胶原蛋白原纤维中，我们的方法已被证明显着 在生长因子的浓度下，改善体内胜利维修的数量级低于 目前使用局部疗法。这些结果，再加上其他的翻译方面的最新进展 基因疗法表明，大衣平台对临床影响的高潜力。 在拟议的R01程序中，我们将在实验DFU和基于细胞的测定中应用大衣 在以下三个目标中，了解编排伤口修复的三个重要方面。在AIM 1中，我们将 CMP修饰的探针变化，以优化基因扩展的递送（最初是针对血小板衍生的 在鼠糖尿病伤口环境中生长因子（PDGF））。在AIM 2中，我们将完成这些研究 通过基于细胞的研究，阐明了MMP（可溶性和膜结合）在调节中的作用 大衣和PDGF蛋白寿命递送PDGF基因。在AIM 3中，我们将测试大衣介导的方式， 免疫调节细胞因子（IL4和IL10）基因的顺序递送可调节DFU中的MMP活性。 这些方法将提供解决DFU的慢性性的机械见解，也是一个新的 可以集成到现有的伤口护理策略中以极大地改善临床结果的平台。