Skin probiotics to treat Netherton Syndrome

皮肤益生菌治疗内瑟顿综合症

基本信息

批准号：
10603536
负责人：
Amin Zargar
金额：
$ 24.99万
依托单位：
RESVITA BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10603536
关键词：
3-Dimensional Adrenal Cortex Hormones Affect Amino Acids Anti-Bacterial Agents Bacteria Cell Survival Childhood Consensus Corynebacterium Corynebacterium glutamicum Data Dehydration Disease Dose Dryness Emollients Engineered skin Engineering Environment Enzymes Equilibrium Evolution FDA approved Foundations Genes Genetic Diseases Genetic Engineering Genetic Models Goals Hair Half-Life Hereditary Disease Home Human Human Volunteers Immune Immune response Immune system In Vitro Infection Kininogenase Laboratories Lysine Microbe Morphology Mus Mutation Mycolic Acid Netherton syndrome Newborn Infant Organism Phase Physiological Pre-Clinical Model Probiotics Process Production Property Proteins Research Safety Sebum Serine Protease Serine Proteinase Inhibitors Site Skin Skin colonization Small Business Innovation Research Grant Soil Stratum corneum Structural Protein Surface Symptoms Therapeutic Tissues Topical application base causal variant delivery vehicle design enzyme replacement therapy extracellular in vitro Model inhibitor innovation metabolic engineering microbial mortality reduce symptoms safety and feasibility skin disorder skin microbiome synthetic biology

项目摘要

Project Summary Netherton syndrome (NS) is a severe genetic disorder that affects the skin, hair, and immune system. NS is caused by mutations associated with the SPINK5 gene which encodes LEKTI (Lympho-epithelial Kazal-type inhibitor), a serine protease inhibitor. Normally, skin shedding is controlled by an extracellular balance between serine proteases and serine protease inhibitors, and mutations in LEKTI result in overactivity of serine proteases. There is not an FDA-approved therapy or consensus treatment of conditions, and symptoms are mostly managed through antibacterials, emollients and corticosteroids. An enzyme-replacement therapy of topically applied LEKTI could be an elegant solution, but the short half-life of LEKTI precludes this possibility. The skin microbiome is home to over 1011 bacteria, and provides an attractive target as a delivery vehicle through continuous delivery of LEKTI. Through synthetic biology, we will engineer a bacteria to colonize the skin surface and secrete bioactive LEKTI to restore balance to the skin shedding process. In this Phase I SBIR, we will establish the safety of our topical application in in vitro models and demonstrate bioactive secretion of LEKTI fragments. This will provide a strong foundation to transition to Phase 2 where we will establish safety and efficacy in murine genetic models.

项目概要内瑟顿综合征 (NS) 是一种严重的遗传性疾病，会影响皮肤、头发和免疫系统。 NS 是由编码 LEKTI（淋巴上皮 Kazal 型）的 SPINK5 基因相关突变引起抑制剂），一种丝氨酸蛋白酶抑制剂。通常，皮肤脱落是由细胞外平衡控制的丝氨酸蛋白酶和丝氨酸蛋白酶抑制剂，LEKTI 突变导致丝氨酸过度活跃蛋白酶。目前还没有 FDA 批准的治疗方法或共识治疗方法，并且症状是主要通过抗菌剂、润肤剂和皮质类固醇来控制。酶替代疗法局部应用 LEKTI 可能是一个优雅的解决方案，但 LEKTI 的半衰期短，排除了这种可能性。皮肤微生物组是超过 1011 种细菌的家园，并提供了一个有吸引力的目标作为递送载体通过持续交付 LEKTI。通过合成生物学，我们将设计一种细菌来定殖皮肤表面分泌生物活性LEKTI，以恢复皮肤脱落过程的平衡。在这个第一阶段 SBIR，我们将在体外模型中建立我们的局部应用的安全性并证明生物活性 LEKTI 片段的分泌。这将为过渡到第二阶段提供坚实的基础，我们将在第二阶段建立小鼠遗传模型的安全性和有效性。