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

这个STTR第一阶段项目旨在建立一个使用工程菌株葡萄球菌(S)的药物输送平台的生存能力。表皮是一种常见的皮肤共生细菌，它可以分泌感兴趣的治疗性蛋白质，以达到治疗皮肤病的最终目标。接种了这种细菌的软膏可以很少地应用于皮肤，提供持续、低成本、方便的就地治疗蛋白输送。这项研究提出了一项概念验证研究，以证明工程菌株表皮葡萄球菌可以作为一种模块化的生物药物输送底盘，可以进行改造以治疗一系列皮肤疾病，从特应性皮炎、Netherton综合征和板层鱼鳞病开始。这些情况代表着跨越常见和罕见疾病的重大商业机会，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，可用于多种来源的不同皮肤疾病，包括遗传性、炎症性和感染性疾病。对拟议目标的验证为吸引人才和投资提供了必要的关键数据，这些人才和投资是建立一家创新、多元化的护肤公司所必需的。该项目具有很高的创新性，因为它提议使用共生皮肤微生物来分泌和传递治疗蛋白质或酶，这些蛋白质或酶要么缺失，要么可能对治疗某些皮肤病有益。目前许多皮肤病的治疗方案旨在缓解症状，但未能解决导致皮肤病的潜在病理生理变化。使用直接局部补充纯化蛋白的方法受到皮下定位差、生产和纯化成本以及持续使用的要求的限制。拟议的第一阶段研究计划将首次确立：(1)共生菌可以作为可调节的、高效的皮肤药物输送系统；(2)可以操纵皮肤共生菌来表达和输出感兴趣的治疗性蛋白质；(3)能够表达异源蛋白质的共生菌可以稳定地在皮肤上定植。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，这些研究将建立治疗皮肤病的药物传递机制的新范式，这也可以扩展到传递广泛的药物以促进皮肤健康。

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.