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.

摘要 这项工作的目标是开发一种治疗不愈合和慢性伤口，将防止伤口 生物膜和促进愈合。慢性伤口影响美国约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%的患者使用 现有的干预措施和许多伤口进展为严重感染，包括截肢。最近的研究 表明超过75%的慢性伤口具有生物膜，生物膜被认为是成功愈合的关键障碍， 治疗越来越多的证据表明，生物膜损害愈合，并与过渡， 伤口进入慢性不愈合状态，涉及耐药生物体和多物种生物膜 在这一过程中，人们越来越认识到这是一个重要因素。目前用于管理的抗菌产品 伤口生物负载不能有效地对抗生物膜和递送可引起刺激、细胞毒性 损害愈合。需要有效对抗生物膜并有助于愈合的新疗法， 可用于减轻疼痛和气味，改善功能结果，并提高生活质量， 慢性创伤 这项工作的目标是开发一种抗菌伤口治疗的基础上工程阳离子 一种称为ASP-2的抗微生物肽，其具有广谱性并且有效对抗生物膜，包括 多重耐药细菌ASP-2对细菌细胞的特异性显著高于宿主细胞 相对于伤口护理中常用的银和其它防腐剂。这提供了更大的生物相容性， 这对于消除创伤消退的障碍和改善愈合是至关重要的。第二阶段项目的目标是建立在 来自I期的强有力的初步数据，确定了先导肽ASP-2的广谱活性， 其在与伤口治疗相关的条件下消除生物膜的能力。在第一阶段， 被开发为用于肽的持续应用和递送的相容载体。ASP-2加载 在挑战性的离体猪皮肤生物膜模型中， 显著降低猪切除感染伤口模型中的生物负荷。在第二阶段，产品 将进一步开发和优化制剂的功效、易用性和储存稳定性。铅制剂 将使用离体猪皮肤生物膜模型针对单一物种和多微生物生物膜进行测试 随后在猪切除感染伤口模型中评价功效和愈合。非临床安全性 将启动包括关键毒性研究和监管策略在内的研究， 将制定发展计划。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。因为伤口治疗的费用 随着关闭时间的推移，该产品还有可能降低总体处理成本。