Topical application of heterologous protein-expressing Staphylococcus epidermidis for potential therapeutic treatment of skin diseases

项目总结 目前一些皮肤病的治疗方案通常旨在缓解症状和 未能解决导致皮肤病的潜在病理生理变化。在.的情况下 导致功能丧失的基因突变、缺失蛋白质的补充 是一种可行的治疗方法。然而，将功能蛋白递送到靶点 角质形成细胞是一个巨大的挑战；此外，蛋白质生产和 提纯为开发商业上可行的治疗方法制造了一个巨大的障碍。最后， 考虑到皮肤的自然周转率，需要不断地重新使用蛋白质， 这加剧了与治疗成本、依从性和便利性相关的问题。 Azitra是一家专注于基于微生物组的治疗的临床前公司。我们正在开发一种 由经过改造的表皮葡萄球菌组成的平台，能够在 人的皮肤和分泌治疗蛋白的原位。接种了这种细菌的药膏 可不经常应用于皮肤，提供恒定、低成本、方便的 治疗性蛋白质。表皮葡萄球菌的自然特性还包括分泌抗菌剂。 抗金黄色葡萄球菌多肽和对调节性T细胞的刺激，使表皮葡萄球菌成为理想的 分泌平台。 拟议的第一阶段研究计划将侧重于概念验证研究，以确定 表皮葡萄球菌生产和输送系统(AIM)的时空生长特征 1)和研究表皮葡萄球菌分泌sGFP的时空动态。 皮肤等效模型(目标2)。在STR第一阶段项目之后的下一阶段(第二阶段)。 该平台的应用将以表皮葡萄球菌分泌的微丝蛋白为基础进行测试。 特应性皮炎的临床模型。

PROJECT SUMMARY Current treatment options for a number of skin diseases generally aim for symptomatic relief and fail to address underlying pathophysiological changes leading to skin disease. In the case of genetic mutations that cause loss of function mutations, supplementation of the missing protein is a viable approach to treatment. However, delivery of functional protein to the target keratinocytes presents a significant challenge; moreover, the cost of protein production and purification creates a significant hurdle to developing a commercially viable treatment. Finally, given the natural turnover rate in the skin, constant reapplication of protein would be needed, which compounds issues related to cost of treatment, adherence, and convenience. Azitra is a preclinical company focused on microbiome-based therapeutics. We are developing a platform that consists of an engineered S. epidermidis that is able to establish residence on human skin and secrete therapeutic protein in situ. An ointment with an inoculum of such bacteria could be infrequently applied to skin, providing constant, low-cost, convenient delivery of therapeutic protein. Natural properties of S. epidermidis also include secretion of antimicrobial peptides against S. aureus and stimulation of regulatory T-cells, making S. epidermidis an ideal secretion platform. The proposed Phase I research plan will focus on proof-of-concept studies to determine the spatio-temporal growth characteristics of our S. epidermidis production and delivery system (Aim 1) and to characterize the spatio-temporal dynamics of sGFP that secreted by S. epidermidis in a skin equivalent model (Aim 2). In the next phase (Phase II) following this STTR Phase I project. The application of this platform will be tested with filaggrin secreted by S. epidermidis in pre- clinical models of atopic dermatitis.