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

表达异源蛋白的表皮葡萄球菌的局部应用对皮肤病的潜在治疗作用

• 批准号: 9202769
• 负责人: LEONARD M MILSTONE
• 金额: $ 15万
• 依托单位: AZITRA, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9202769
• 关键词: Address; Anti-Inflammatory Agents; Antibiotics; Atopic Dermatitis; Bacteria; Bacterial Proteins; Biological Assay; Biological Models; Businesses; Calcineurin inhibitor; Cells; Characteristics; Chronic; Confocal Microscopy; Coupled; DNA Sequence Alteration; Data; Defect; Dermal; Development; Disease; Ecology; Engineering; Epidermis; Experimental Designs; Gene Mutation; Genes; Genetic; Genetic Skin Diseases; Grant; Growth; Health Care Costs; Histology; Human; Ichthyosis Vulgaris; Image; Immunohistochemistry; In Situ; In Vitro; Inflammatory; Location; Measures; Modeling; Mutation; Ointments; Patients; Penetration; Peptides; Phase; Physiology; Population; Pre-Clinical Model; Predisposition; Production; Property; Protein Export Pathway; Proteins; Reapplication; Recombinants; Regulatory T-Lymphocyte; Research; Resolution; Role; Signal Transduction; Skin; Small Business Technology Transfer Research; Staging; Staphylococcus aureus; Staphylococcus epidermidis; Stratum corneum; Structure; Supplementation; System; Testing; Therapeutic; Therapeutic Uses; Time; Topical Corticosteroids; Topical application; Universities; antimicrobial peptide; base; cost; expression vector; filaggrin; imaging system; in vitro Model; interest; keratinocyte; loss of function mutation; microbial; microbiome; novel strategies; pre-clinical; residence; skin barrier; skin disorder; skin microbiome; therapeutic protein; treatment adherence

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.

项目摘要 目前对许多皮肤病的治疗选择通常旨在缓解症状， 未能解决导致皮肤病的潜在病理生理学变化。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，将功能性蛋白质递送至靶点是不可能的。 角质形成细胞提出了一个重大的挑战;此外，蛋白质生产的成本和 纯化对开发商业上可行的处理产生了显著的障碍。最后， 考虑到皮肤中的自然更新速率，需要不断地重新施用蛋白质， 这使得与治疗成本、依从性和便利性相关的问题更加复杂。 Azitra是一家临床前公司，专注于基于微生物组的治疗。我们正在开发一个 该平台由一个工程化的S。表皮细胞能够在 并原位分泌治疗性蛋白质。接种了这种细菌的药膏 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S.表皮也包括分泌抗菌物质 抗S.金黄色葡萄球菌和刺激调节性T细胞，使S. epidermidis一个理想 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 时空生长特征。表皮生成和递送系统（Aim 1)并对S.表皮内 皮肤等效模型（目标2）。在STTR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S.表皮在前， 特应性皮炎的临床模型。