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

• 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
• 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

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了数百万美国公民的生活质量，并且与并发症的风险增加有关，包括截肢的毁灭性后果。截至2006年，糖尿病足溃疡的感染每年导致82,000次截肢，据估计，这些数字每年增加10％。此外，在对几种类型的慢性伤口（包括糖尿病足溃疡，静脉腿溃疡和压溃疡）的广泛研究中，发现60％含有细菌性生物膜。美国国立卫生研究院估计，80％的人类传染病与细菌生物膜形成直接相关。此外，广泛认识到细菌生物膜对抗生素治疗具有高度抗性。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，迫切需要在这些伤口中破坏生物膜形成的新型策略。 这项快速轨道SBIR转化研究建议的具体目的旨在推动Expressgraftenhance组织的发展，这是Stratatech Corporation创建的一种抗菌活性皮肤替代品，已被证明抑制了在体内燃烧感染模型中抑制多药抗性细菌的生长（Mol.2009 Mar; 17 Mar; 17 Mar; 17（3月17日）：562-9：562-9：562-9：562-9。562-9。 Stratatech与行业，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在预防或破坏多种耐药细菌的生物膜形成方面的有效性。第一阶段的里程碑将1）证明由Expressgraftenhance分泌的HCAP-18/LL-37在体外对生物膜形成有效，2）开发效力分析以监测这种生物活性和3）优化这种生物替代皮肤组织的理想生产和存储条件。第二阶段研究将：1）确定在预防或破坏细菌生物膜形成的功效表达组织体外形成，2）表明，在鼠类和猪在体内生物膜伤害模型的生物膜伤害模型和4）生物膜伤害的生物膜伤害，并实施CGMP的生物损伤模型，3）用于创建Expressgraftenhance的晚期通道细胞是核型稳定的，非肿瘤的，不含病毒的不定剂，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，以用于治疗因细菌定植和伤口病原体形成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临床前数据，以支持将Expressgraftenhance技术转化为人类临床试验。 细菌生物膜最近已被医学界认识到伤口愈合的重大障碍，美国国立卫生研究院估计，80％的人类感染性疾病与细菌生物膜形成直接相关，但没有生物治疗方案，而没有专门针对生物膜感染的生物学治疗方案。这种翻译快速轨道SBIR提案的目的是建立一系列协作伙伴关系，以加快创新抗菌治疗的开发，旨在通过防止或破坏由多药耐药细菌形成的伤口来加速伤口的愈合。专门设计用于破坏生物膜的培养人皮肤替代品的发展将针对数百万患有难以愈合的皮肤伤口的患者的需求，这既可以消除愈合的障碍，同时又可以促进愈合，减轻疼痛，并减少其他重大并发症的可能性。