Development of an Antimicrobial Cellular Therapeutic for Inhibition of Biofilm Fo

开发用于抑制生物膜 Fo 的抗菌细胞疗法

基本信息

批准号：
7989090
负责人：
Allen R. Comer
金额：
$ 50万
依托单位：
STRATATECH CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7989090
关键词：
Academia Achievement Acute Advanced Development Affect Amputation Animal Model Antibiotic Resistance Antibiotic Therapy Bacteria Biological Biological Assay Biology Biomanufacturing Burn injury CAP18 lipopolysaccharide-binding protein Cells Chronic Clinical Clinical Research Clinical Trials Commit Communicable Diseases Communities Contracts Cutaneous Cyclic GMP Data Decubitus ulcer Development Diabetic Foot Ulcer Effectiveness Engineering Evaluation Family suidae Goals Growth Healed Human Impaired wound healing In Vitro Industry Infection Institutes Leg Ulcer Life Marketing Measures Medical Microbial Biofilms Military Personnel Modeling Monitor Multi-Drug Resistance Mus Pain Pathology Patients Phase Planet Mars Process Production Qualifying Quality of life Refractory Research Research Proposals Resistance Risk Secure Series Skin Skin Substitutes Skin Tissue Small Business Innovation Research Grant Technology Testing Therapeutic Tissues Transgenes Translational Research Translations Tumorigenicity United States National Institutes of Health Universities Venous Viral Wisconsin Wound Healing Wound Infection antimicrobial antimicrobial peptide arm base design drug resistant bacteria drug resistant microorganism healing improved in vivo innovation keratinocyte manufacturing process novel novel strategies pathogen phase 2 study pre-clinical preclinical safety prevent response tissue processing tumorigenic wound

项目摘要

DESCRIPTION (provided by applicant): Chronic and infected wounds significantly affect the quality of life for millions of US citizens and are associated with increased risk of complications including the devastating consequence of amputation. As of 2006, infections of diabetic foot ulcers resulted in 82,000 amputations each year and it has been estimated that these numbers will increase by 10% annually. Moreover, in an extensive study of several types of chronic wounds including diabetic foot ulcers, venous leg ulcers, and pressure ulcers, 60% were found to contain bacterial biofilms. The National Institutes of Health estimates that 80% of human infectious diseases are directly related to bacterial biofilm formation. Furthermore, it is widely recognized that bacterial biofilms are highly resistant to antibiotic treatment. There is a growing body of evidence indicating that biofilm formation acts as a major impediment to the healing of cutaneous wounds. Accordingly, there is an urgent need for novel strategies to disrupt biofilm formation in these wounds. The specific aims for this Fast-Track SBIR translational research proposal are designed to advance the development of ExpressGraftEnhance tissue, an antimicrobial living skin substitute created by Stratatech Corporation that has been shown to inhibit the growth of multidrug-resistant bacteria in an in vivo burn infection model (Mol Ther. 2009 Mar;17(3):562-9). Stratatech has established an interdisciplinary series of collaborative partnerships with industry, academia, and the U.S. armed forces to test ExpressGraftEnhance its effectiveness in preventing or disrupting biofilm formation by multidrug-resistant bacteria. Phase I milestones will 1) demonstrate that hCAP-18/LL-37 secreted by ExpressGraftEnhance is efficacious against biofilm formation in vitro, 2) develop potency assays to monitor this bioactivity and 3) optimize ideal production and storage conditions for this living skin substitute tissue. The Phase II study will: 1) determine the efficacy ExpressGraftEnhance tissue in preventing or disrupting bacterial biofilm formation in vitro, 2) demonstrate the efficacy of ExpressGraftEnhance tissue against biofilm formation in both murine and porcine in vivo wound models of biofilm infection, 3) implement and qualify cGMP manufacturing processes and potency assays for ultimate clinical use and 4) demonstrate that late passage cells used to create ExpressGraftEnhance are karyotypically stable, non-tumorigenic, free of viral adventitious agents, and maintain transgene stability and integrity. Stratatech's ultimate goal is to commercialize the ExpressGraftEnhance skin substitute for use in treating cutaneous wounds that are refractory to healing due to bacterial colonization and biofilm formation by wound pathogens. The studies of this proposal are designed to generate preclinical data that are required to support translation of the ExpressGraftEnhance technology into human clinical trials. Bacterial biofilms have become recently become recognized by the medical community as significant barriers to wound healing, and the National Institutes of Health estimates that 80% of human infectious diseases are directly related to bacterial biofilm formation yet no biological treatment options that specifically target biofilm infection have been developed and marketed. The goal of this translational Fast-Track SBIR proposal is to develop a series of collaborative partnerships to expedite the development of an innovative antimicrobial therapeutic aimed at accelerating the healing of wounds by preventing or disrupting wound biofilms formed by multidrug-resistant bacteria. The development of a cultured human skin substitute specifically engineered to disrupt biofilms would target the needs of the millions of patients afflicted with hard-to-heal skin wounds by both eliminating the impediment to healing while also promoting healing, reducing pain, and reducing the likelihood of other major complications.

描述（由申请人提供）：慢性和感染的伤口严重影响数百万美国公民的生活质量，并与并发症风险增加相关，包括截肢的破坏性后果。截至 2006 年，每年因糖尿病足溃疡感染导致 82,000 例截肢，预计这一数字将以每年 10% 的速度增长。此外，在对几种类型的慢性伤口（包括糖尿病足溃疡、腿部静脉溃疡和压疮）进行的广泛研究中，发现 60% 的慢性伤口含有细菌生物膜。美国国立卫生研究院估计，80%的人类传染病与细菌生物膜的形成直接相关。此外，人们普遍认为细菌生物膜对抗生素治疗具有高度耐药性。越来越多的证据表明，生物膜的形成是皮肤伤口愈合的主要障碍。因此，迫切需要新的策略来破坏这些伤口中生物膜的形成。这项 Fast-Track SBIR 转化研究提案的具体目标是促进 ExpressGraftEnhance 组织的开发，这是一种由 Stratatech Corporation 创建的抗菌活体皮肤替代品，已被证明可以抑制体内烧伤感染中多重耐药细菌的生长模型（Mol Ther. 2009 Mar；17(3):562-9）。 Stratatech 与工业界、学术界和美国武装部队建立了一系列跨学科的合作伙伴关系，以测试 ExpressGraftEnhance 其预防或破坏多重耐药细菌生物膜形成的有效性。 I 期里程碑将 1) 证明 ExpressGraftEnhance 分泌的 hCAP-18/LL-37 可有效抑制体外生物膜形成，2) 开发效力测定来监测这种生物活性，3) 优化这种活体皮肤替代组织的理想生产和储存条件。 II 期研究将：1) 确定 ExpressGraftEnhance 组织在体外预防或破坏细菌生物膜形成的功效，2) 证明 ExpressGraftEnhance 组织在生物膜感染的小鼠和猪体内伤口模型中对抗生物膜形成的功效，3) 实施并验证 cGMP 制造工艺和效力测定以供最终临床使用，4) 证明用于创建 ExpressGraftEnhance 的晚期传代细胞核型稳定、非致瘤性、不含病毒外源因子，并保持转基因的稳定性和完整性。 Stratatech 的最终目标是将 ExpressGraftEnhance 皮肤替代品商业化，用于治疗由于伤口病原体的细菌定植和生物膜形成而难以愈合的皮肤伤口。该提案的研究旨在生成支持将 ExpressGraftEnhance 技术转化为人体临床试验所需的临床前数据。细菌生物膜最近已被医学界认为是伤口愈合的重大障碍，美国国立卫生研究院估计 80% 的人类传染病与细菌生物膜的形成直接相关，但目前还没有专门针对生物膜感染的生物治疗方案。已被开发并上市。这项转化性快速通道 SBIR 提案的目标是建立一系列合作伙伴关系，以加快创新抗菌疗法的开发，旨在通过预防或破坏由多重耐药细菌形成的伤口生物膜来加速伤口愈合。开发一种专门用于破坏生物膜的培养人类皮肤替代品，将能够满足数百万皮肤伤口难以愈合患者的需求，消除愈合障碍，同时促进愈合，减轻疼痛，并降低伤口愈合的可能性。其他主要并发症。