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

基本信息

批准号：
10459594
负责人：
Kristi L Kiick
金额：
$ 45.66万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
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/10459594
关键词：
Address Amputation Behavior Behavior Control Biocompatible Materials Biological Assay Cells Cessation of life Chromosome Mapping Chronic Climate Clinical Collagen Collagen Fibril Complement Complex Coupled Cytokine Gene DNA Data Diabetic Foot Ulcer Dose Engineering Environment Equilibrium Etiology Exudate Fibroblasts Gene Delivery Gene Expression Gene Transfer Gene-Modified Genes Growth Factor Growth Factor Gene Half-Life Health Human IL4 gene Immunology Incidence Inflammatory Interleukin-10 Investigation Leg Link MMP14 gene Matrix Metalloproteinases 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 base chronic wound cost cytokine design diabetic ulcer economic impact gene product gene therapy healing health economics immunoregulation improved in vivo inflammatory milieu innovation insight macrophage 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

项目摘要

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) 是一个代价高昂的全球健康问题。仅在美国每年就导致近 80,000 例小腿截肢，并且与显着相关增加死亡可能性的策略已成为深入研究的主题。几十年来，无数的细胞和病理生理学异常仍然严重限制了有前景的治疗替代方案包括细胞支架的应用、局部治疗。生长因子（尤其是血小板衍生生长因子）或组合伤口敷料。完全闭合的发生率仍然惊人地低，并且生长因子输送策略基本上失败，原因是它们在慢性伤口的炎症、富含 MMP 的环境中不稳定。通过刺激治疗性蛋白质的局部产生，使蛋白水解和炎症环境正常化因此，通过成纤维细胞和巨噬细胞，将为改善临床结果提供一种激发方法。我们最近证明，可以利用伤口床中的蛋白酶活性刺激局部生长因子基因传递并提供生长因子的可定制表达我们在数周的时间范围内引入了胶原模拟肽 (CMP) 和治疗性基因修饰。胶原蛋白（COAT）作为平台，用于（i）在胶原蛋白中牢固保留编码生长因子的复合物- 包含伤口敷料和（ii）胶原蛋白重塑过程中局部、细胞启动的基因传递。 COAT 将 DNA 复合物直接整合到胶原纤维中，我们的方法已被证明可以显着在生长因子浓度比体内低几个数量级的情况下改善体内伤口修复目前采用的局部疗法，再加上其他疗法的最新进展。基因疗法表明 COAT 平台具有巨大的临床影响潜力。在拟议的 R01 计划中，我们将在实验 DFU 和基于细胞的测定中应用 COAT 在目标 1 中，我们将了解管弦乐队伤口修复的三个重要方面，在以下三个目标中。 CMP 修饰中的探针变化可优化基因的延长传递（最初用于血小板衍生的在目标 2 中，我们将补充这些研究。基于细胞的研究阐明了 MMP（可溶性和膜结合性）在调节中的作用通过 COAT 进行 PDGF 基因传递和 PDGF 蛋白寿命在目标 3 中，我们将测试 COAT 如何介导，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。这些方法将为解决 DFU 的长期性提供机制见解，并提供新的方法该平台可以集成到伤口现有护理策略中，以显着改善临床结果。