STTR Phase I: Re-engineered skin bacteria as a novel topical drug delivery system

STTR 第一阶段：重新设计皮肤细菌作为新型局部给药系统

• 批准号: 1648819
• 负责人: Travis Whitfill
• 金额: $ 22.5万
• 依托单位: Azitra Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1648819&HistoricalAwards=false
• 关键词: STTR; Phase; Re; engineered; skin

This STTR Phase I project aims to establish the viability of a drug delivery platform that employs an engineered strain of Staphylococcus (S.) epidermidis, a common skin commensal bacterium, that can secrete therapeutic proteins of interest for the ultimate goal of treating skin disease. An ointment with an inoculum of such bacteria could be infrequently applied to skin, providing constant, low-cost, convenient delivery of therapeutic protein in situ. This study proposes proof-of-concept studies to demonstrate that an engineered strain of S. epidermidis can serve as a modular, biological drug delivery chassis that can be modified to treat a range of skin conditions, beginning with atopic dermatitis, Netherton Syndrome, and lamellar ichthyosis. These conditions represent significant commercial opportunities spanning both common and rare diseases, and provide validation for a generalized engineered platform of skin bacteria with broad potential applicability to different skin disorders of multifaceted origin, including genetic, inflammatory, and infectious disorders. Validation of the proposed targets provides the crucial data necessary to attract the talent and investment necessary to build an innovative, diversified skin care company. This project is highly innovative because it proposes using commensal skin microbes to secrete and deliver therapeutic proteins or enzymes that are either missing or could be beneficial in treating certain skin diseases. Current treatment options for many skin diseases aim for symptomatic relief and fail to address underlying pathophysiological changes leading to skin disease. Approaches using direct topical supplementation of purified protein are limited by poor subcutaneous localization to sites of need, production and purification costs, and a requirement for constant application. The proposed Phase I research plan will establish for the first time that (1) commensal bacteria can serve as tunable and highly potent drug delivery systems in the skin; (2) skin commensal bacteria can be manipulated to express and export a therapeutic protein of interest; and (3) commensal bacteria engineered to expresses heterologous proteins can colonize skin stably. This project will be executed using both standard molecular biology tools such as cloning and spectrophotometric analysis as well as advanced methods in confocal imaging and synthetic biology. Together, these studies will establish a new paradigm in drug delivery mechanisms for the treatment of skin diseases, which can also be extended to delivery of broad array of agents to promote skin health.

该STTR I期项目旨在建立采用葡萄球菌（S.）工程菌株的药物递送平台的可行性。表皮葡萄球菌是一种常见的皮肤细菌，其可以分泌感兴趣的治疗性蛋白质，用于治疗皮肤疾病的最终目标。 具有这种细菌的接种物的软膏剂可以不经常地应用于皮肤，提供恒定的、低成本的、方便的治疗性蛋白质原位递送。这项研究提出了概念验证研究，以证明S。表皮可用作模块化的生物药物递送底盘，其可被修饰以治疗一系列皮肤病症，开始于特应性皮炎、内瑟顿综合征和板层鱼鳞病。这些条件代表了跨越常见和罕见疾病的重要商业机会，并为皮肤细菌的通用工程平台提供了验证，该平台具有广泛的潜在适用性，可用于多方面起源的不同皮肤疾病，包括遗传性，炎症性和感染性疾病。对拟议目标的验证提供了必要的关键数据，以吸引必要的人才和投资，建立一个创新的，多元化的护肤品公司。该项目具有高度创新性，因为它提出使用皮肤微生物来分泌和提供治疗性蛋白质或酶，这些蛋白质或酶在治疗某些皮肤疾病时缺失或可能有益。目前许多皮肤病的治疗方案旨在缓解症状，未能解决导致皮肤病的潜在病理生理变化。使用纯化蛋白质的直接局部补充的方法受限于对需要部位的皮下定位差、生产和纯化成本以及持续应用的要求。拟议的第一阶段研究计划将首次确定：（1）皮肤细菌可以作为皮肤中可调和高效的药物递送系统;（2）皮肤细菌可以被操纵以表达和输出感兴趣的治疗蛋白质;（3）经工程改造以表达异源蛋白质的皮肤细菌可以稳定地定殖皮肤。该项目将使用克隆和分光光度分析等标准分子生物学工具以及共聚焦成像和合成生物学的先进方法来执行。总之，这些研究将为治疗皮肤病的药物递送机制建立一个新的范例，这也可以扩展到广泛的药物递送，以促进皮肤健康。