Skin probiotics to treat Netherton Syndrome

项目摘要 内瑟顿综合征（NS）是一种严重的遗传性疾病，影响皮肤，头发和免疫系统。NS是 由与编码LEKTI（上皮细胞Kazal型）的SPINK5基因相关的突变引起 抑制剂），丝氨酸蛋白酶抑制剂。正常情况下，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，以及LEKTI中的突变导致丝氨酸蛋白酶的过度活性， 蛋白酶没有FDA批准的治疗或共识治疗条件，症状是 主要通过抗菌剂润肤剂和皮质类固醇治疗。酶替代疗法 局部应用LEKTI可能是一个优雅的解决方案，但LEKTI的短半衰期排除了这种可能性。 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 通过持续提供LEKTI。通过合成生物学，我们将设计一种细菌， 并分泌生物活性LEKTI，恢复皮肤脱落过程的平衡。这项I期 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奠定坚实的基础， 在鼠遗传模型中建立安全性和有效性。

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.