Antimicrobial Peptide Treatment to Combat Wound Biofilm

对抗伤口生物膜的抗菌肽治疗

• 批准号: 10223891
• 负责人: Jennifer Ann Neff
• 金额: $ 64.62万
• 依托单位: ALLVIVO VASCULAR, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-07 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223891
• 关键词: 3-Dimensional; Affect; Amputation; Antibiotics; Antimicrobial Cationic Peptides; Bacteria; Blood; Blood Vessels; Caring; Cells; Chitosan; Chronic; Crowding; Data; Dermal; Development; Development Plans; Dose; Drug resistance; Engineering; Evaluation; Excision; Family suidae; Formulation; Foundations; Freezing; Goals; Government; Health Care Costs; Impaired healing; Infection; Intervention; Iodine; Lead; Literature; Local Anti-Infective Agents; Measures; Methods; Microbial Biofilms; Miniature Swine; Modeling; Morbidity - disease rate; Multiple Bacterial Drug Resistance; Odors; Organism; Pain; Patients; Peptides; Perfusion; Persons; Phase; Process; Pseudomonas aeruginosa; Quality of life; Rattus; Recovery; Research; Risk; Safety; Silver; Site; Skin; Specificity; Sterilization; Testing; Time; Tissues; Toxic effect; Toxicology; Treatment Cost; Work; Wound Infection; Wound models; analytical method; antimicrobial; antimicrobial peptide; base; biomaterial compatibility; chronic wound; combat wound; cost; cytotoxicity; drug resistant bacteria; efficacy evaluation; functional outcomes; healing; immunogenicity; improved; in vivo; irritation; methicillin resistant Staphylococcus aureus; non-healing wounds; novel therapeutics; pain reduction; polymicrobial biofilm; porcine model; prevent; programs; repaired; safety study; stem; subcutaneous; success; wound; wound biofilm; wound care; wound closure; wound healing; wound treatment

ABSTRACT The goal of this work is to develop a treatment for non-healing and chronic wounds that will prevent wound biofilm and facilitate healing. Chronic wounds affect approximately 6.5 million patients in the US with annual treatment cost up to $50 billion. Despite high treatment costs, approximately 30% of patients will not heal using existing interventions and many wounds progress to serious infections, including amputation. Recent studies indicate that over 75% of chronic wounds harbor biofilms, which is considered a key barrier to successful treatment. There is increasing evidence that biofilms impair healing and are associated with the transition of wounds to a chronic non-healing state with the involvement of drug resistant organisms and multispecies biofilms is gaining recognition as an important factor in this process. Current antimicrobial products used to manage wound bioburden are not effective against biofilm and deliver agents that can cause irritation, cytotoxicity and impair healing. New therapeutics are needed that are effective against biofilms and conducive to healing that can be used to reduce pain and odor, improve functional outcomes, and improve quality of life for those with chronic wounds. The goal of this work is to develop an antimicrobial wound treatment based on an engineered cationic antimicrobial peptide called ASP-2 that is broad spectrum and effective against biofilms including those of multidrug resistant bacteria. ASP-2 displays significantly greater specificity for bacteria cells versus host cells relative to silver and other antiseptics commonly used in wound care. This provides greater biocompatibility, which is critical to remove barriers to wound resolution and improve healing. The Phase II project aims build on strong preliminary data from Phase I that established the broad-spectrum activity of a lead peptide, ASP-2, and its capacity to eradicate biofilms under conditions relevant to wound treatment. In Phase I, chitosan formulations were developed as a compatible vehicle for sustained application and delivery of the peptide. ASP-2 loaded formulations were shown to be effective against biofilms in a challenging ex vivo porcine skin biofilm model and in significantly reducing bioburden in a porcine excisional infected wound model. In Phase II, the product formulation will be further developed and optimized for efficacy, ease of use, and shelf stability. Lead formulations will be tested against single species and polymicrobial biofilms using an ex vivo porcine skin biofilm model followed by an evaluation of efficacy and healing in a porcine excisional infected wound model. Nonclinical safety studies will be initiated including key toxicity studies and a regulatory strategy with a detailed nonclinical development plan will be prepared. Success of this project will have a significant impact on reducing morbidity and improving the quality of life of patients with chronic wounds. Because the cost of wound treatment scales with time to closure, the product also has potential to reduce overall treatment costs.

抽象的 这项工作的目的是开发针对非污染和慢性伤口的治疗方法，以防止伤口 生物膜并促进愈合。慢性伤口在美国影响约650万患者 治疗费用高达500亿美元。尽管治疗费用很高，但大约30％的患者不会使用 现有的干预措施和许多伤口发展为严重的感染，包括截肢。最近的研究 表明超过75％的慢性伤口藏有生物膜，这被认为是成功的关键障碍 治疗。越来越多的证据表明生物膜会损害愈合，并且与 慢性非治疗状态的伤口与耐药性生物和多种物种生物膜有关 在此过程中，人们成为认识的重要因素。当前用于管理的抗菌产品 伤口生物负担对生物膜无效，并递送可能引起刺激，细胞毒性和 损害康复。需要新的治疗剂，这些治疗剂有效地抵抗生物膜，并有利于治愈 可用于减轻疼痛和气味，改善功能结果，并改善患有 慢性伤口。 这项工作的目的是基于工程阳离子开发抗菌伤口治疗 称为ASP-2的抗菌肽，它是广泛且对生物膜有效的抗菌肽，包括 多药耐药细菌。 ASP-2显示细菌细胞与宿主细胞的特异性明显更高 相对于在伤口护理中常用的银和其他防腐剂。这提供了更大的生物相容性， 这对于消除伤口分辨率并改善愈合的障碍至关重要。第二阶段项目的目标是 第一阶段的强大初步数据确定了铅肽，ASP-2和 它在与伤口治疗有关的条件下根除生物膜的能力。在第一阶段，壳聚糖配方 是作为兼容肽的兼容车辆而开发的。 ASP-2加载 在充满挑战的外猪皮肤生物膜模型中，配方显示对生物膜有效，并且 在显着降低猪e裂感染伤口模型中的生物负担。在第二阶段，产品 配方将进一步开发和优化，以效果，易用性和货架稳定性。铅配方 将使用离体猪皮肤模型对单个物种和多生物生物膜进行测试 然后评估猪的感染伤口模型中功效和愈合。非临床安全 将开始研究，包括关键的毒性研究和具有详细非临床的监管策略 开发计划将准备。该项目的成功将对降低发病率产生重大影响 并改善慢性伤口患者的生活质量。因为伤口治疗量表的成本 随着时间的关闭，该产品还具有降低总体治疗成本的潜力。