Skin probiotics to treat atopic dermatitis

项目摘要 特应性皮炎（AD）是一种常见的慢性炎症性皮肤病， 干燥发痒的伤口目前的治疗，包括免疫调节剂和抗炎药 类固醇，有时可以控制症状，但也可能有严重的副作用， 提供长期治疗。这些治疗可能是不够的，因为它们没有解决 皮肤屏障失效在AD发展中的最初作用，这可能导致一个循环， 炎症、致敏和感染。据信AD中对皮肤屏障的损害 由过度的丝氨酸蛋白酶活性加剧或引起。适当的蛋白水解活性是 对于维持皮肤屏障是必需的，并通过蛋白水解调节， 角蛋白桥粒，其主要由激肽释放酶相关肽酶（KLK）进行。 KLK 5、7和14是表皮中的核心蛋白水解酶，并被LEKTI抑制 （淋巴上皮Kazal型相关抑制剂）片段。 过量的丝氨酸蛋白酶活性，特别是来自KLK 5和KLK 7的丝氨酸蛋白酶活性，被认为是一个潜在的原因。 AD的主要原因然而，纠正皮肤中的这种过度蛋白水解是困难的，因为 该器官中的许多稳态途径由蛋白酶控制，需要特异性的 以最小的抗原性进行调节。使用LEKTI的酶替代品尚未被广泛使用。 成功的原因是施用的局部肽被许多外切和内切肽快速降解， 存在于皮肤中的内切蛋白酶。因此，大多数KLK抑制剂的努力涉及修饰 天然肽抑制剂，以保持其活性，同时增加其寿命。这些小 分子药物模拟物由于全身吸收可能具有显著的毒性问题。 我们建议，使用基因工程局部细菌的现场酶 更换可以有效地应对这些挑战。我们的目标是通过基因工程 无害细菌暂时填充皮肤微生物组并提供激肽释放酶抑制剂 治疗AD。我们在皮肤表面连续生产肽类药物的平台， 有可能彻底改变特应性皮炎的治疗。 在第一阶段SBIR中，我们将确定局部应用的安全性， 证明了我们的目标抑制剂的生物活性分泌。这将提供一个坚实的基础， 过渡到II期，我们将在小鼠遗传模型中确定安全性和有效性。

Project Summary Atopic dermatitis (AD) is a common, chronic inflammatory skin condition characterized by dry, itchy lesions. Current treatments, including immunomodulators and anti-inflammatory steroids, can sometimes control symptoms but may also have serious side effects and do not offer a long-term cure. These treatments may be insufficient because they do not address the initial role of skin barrier failure in the development of AD, which can lead to a cycle of inflammation, sensitization, and infection. It is believed that the damage to the skin barrier in AD is exacerbated or caused by excessive serine protease activity. Proper proteolytic activity is essential for maintaining the skin barrier and is regulated by proteolysis of the corneodesmosomes, which is predominantly carried out by kallikrein-related peptidases (KLKs). KLK5, 7, and 14 are the core proteolytic enzymes in the epidermis and are inhibited by LEKTI (lympho-epithelial Kazal-type-related inhibitor) fragments. Excessive serine protease activity, particularly from KLK5 and KLK7, is thought to be a primary cause of AD. However, correcting this excess proteolysis in the skin is difficult because many homeostatic pathways in this organ are controlled by proteases, requiring specific modulation with minimal antigenicity. Enzyme replacement using LEKTI has not yet been successful because applied topical peptides are quickly degraded by the many exo- and endo-proteases present in the skin. Therefore, most KLK inhibitor efforts involve modifying natural peptide inhibitors to maintain their activity while increasing their lifetime. These small molecule drug mimics may have significant toxicity concerns due to systemic absorption. We propose that the use of genetically engineered topical bacteria for on-site enzyme replacement could effectively address these challenges. We aim to genetically engineer a harmless bacterium to temporarily populate the skin microbiome and deliver kallikrein inhibitors to treat AD. Our platform for continuous production of peptide drugs on the skin surface has the potential to revolutionize the treatment of atopic dermatitis. In this Phase I SBIR, we will establish the safety of our topical application and demonstrate bioactive secretion of our target inhibitors. This will provide a strong foundation to transition to Phase 2 where we will establish safety and efficacy in murine genetic models.