Skin probiotics to treat atopic dermatitis

皮肤益生菌治疗特应性皮炎

• 批准号: 10760367
• 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
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10760367
• 关键词: Address; Affect; American; Anti-Inflammatory Agents; Atopic Dermatitis; Automobile Driving; Bacteria; California; Cathepsins; Complex; Corynebacterium; Corynebacterium glutamicum; Development; Disease; Dryness; Engineered skin; Engineering; Environment; Environmental Risk Factor; Enzymes; Epidermis; Evolution; Failure; Foundations; Genetic; Genetic Engineering; Genetic Models; Goals; Growth; Half-Life; Human; Immune; Immune response; Immunomodulators; In Vitro; Industry; Infection; Inflammation; Inflammatory; Investigation; Kininogenase; Laboratories; Lesion; Metalloproteases; Microbe; Modality; Modeling; Mus; Organ; Organism; Pathologic; Pathway interactions; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Probiotics; Production; Protease Inhibitor; Proteins; Proteolysis; Role; Safety; San Francisco; Sebum; Serine Protease; Serine Proteinase Inhibitors; Site; Skin; Small Business Innovation Research Grant; Soil; Staphylococcus epidermidis; Steroids; Stratum corneum; Surface; Symptoms; Testing; Therapeutic Effect; Tissue Model; Tissues; Topical application; Toxic effect; Transgenic Organisms; Universities; absorption; chronic inflammatory skin; enzyme replacement therapy; extracellular; human model; in vivo; inhibitor; innovation; metabolic engineering; microbial; mouse model; novel; peptide drug; safety and feasibility; side effect; skin barrier; skin disorder; skin microbiome; small molecule; synthetic biology; targeted treatment; therapeutic protein

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.

项目摘要 特应性皮炎(AD)是一种常见的慢性炎症性皮肤疾病 又干又痒的皮损。目前的治疗方法，包括免疫调节剂和抗炎药物 类固醇，有时可以控制症状，但也可能有严重的副作用 提供一种长期的治疗方法。这些治疗方法可能是不够的，因为它们没有解决 皮肤屏障失效在阿尔茨海默病发展中的初始作用，可导致循环 炎症、敏感化和感染。据认为，AD对皮肤屏障的破坏 因丝氨酸蛋白酶活性过高而加重或引起。适当的蛋白质分解活性是 对维持皮肤屏障是必不可少的，由蛋白质分解调节 新桥粒，主要由激肽释放酶相关的多肽酶(KLK)执行。 KLK5、7和14是表皮中的核心蛋白水解酶，被lekti抑制。 (淋巴上皮型Kazal相关抑制物)片段。 丝氨酸蛋白酶活性过高，特别是KLK5和KLK7，被认为是一种 阿尔茨海默病的主要原因。然而，纠正皮肤中这种过度的蛋白质分解是困难的，因为 这个器官中的许多动态平衡途径都是由蛋白酶控制的，需要特定的 以最小的抗原性进行调制。使用lekti的酶替代技术还没有被 成功是因为应用的局部多肽很快就会被许多外源和 存在于皮肤中的内切酶。因此，大多数KLK抑制剂的努力涉及到修改 天然多肽抑制剂，以保持其活性，同时延长其寿命。这些小的 由于全身吸收，分子药物模拟物可能有显著的毒性问题。 我们建议使用基因工程局部细菌制作现场酶 替代可以有效地应对这些挑战。我们的目标是从基因上设计一种 暂时填充皮肤微生物群并提供激肽释放酶抑制剂的无害细菌 治疗阿尔茨海默病。我们在皮肤表面连续生产多肽药物的平台 有可能彻底改变特应性皮炎的治疗方法。 在第一阶段SBIR中，我们将确定我们的局部应用的安全性，并 展示我们的目标抑制剂的生物活性分泌。这将为以下工作提供坚实的基础 过渡到第二阶段，在那里我们将在小鼠遗传模型中建立安全性和有效性。