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皮肤状况 干燥，发痒的病变。当前治疗，包括免疫调节剂和抗炎 类固醇有时会控制症状，但也可能有严重的副作用，而不会 提供长期治愈。这些治疗可能不足，因为它们没有解决 皮肤屏障故障在AD开发中的初始作用，这可能导致一个周期 炎症，敏化和感染。据信，AD中皮肤屏障的损害 由过度的丝氨酸​​蛋白酶活性加重或引起。适当的蛋白水解活性是 维持皮肤屏障至关重要，并受到蛋白水解的调节 角膜小体，主要由Kallikrein相关肽酶（KLKS）进行。 KLK5、7和14是表皮中的核心蛋白水解酶，并被Lekti抑制 （淋巴上皮 - 卡扎尔型抑制剂）片段。 过多的丝氨酸蛋白酶活性，特别是来自KLK5和KLK7的活动，被认为是一种 AD的主要原因。但是，纠正皮肤中的多余蛋白水解是困难的，因为 该器官中的许多稳态途径都由蛋白酶控制，需要特定 调节抗原性最小。使用Lekti替换酶尚未 成功，因为应用的局部肽很快被许多外来和 皮肤中存在内蛋白酶。因此，大多数KLK抑制剂的工作涉及修改 天然肽抑制剂在增加其寿命的同时保持活性。这些很小 分子药物模拟物可能由于全身吸收而具有明显的毒性问题。 我们建议将基因设计的局部细菌用于现场酶 替换可以有效解决这些挑战。我们的目标是基因工程 无害细菌以暂时填充皮肤微生物组并提供Kallikrein抑制剂 治疗广告。我们在皮肤表面连续生产肽药物的平台具有 革新特应性皮炎的潜力。 在此阶段I SBIR中，我们将建立我们的局部应用的安全性 证明我们靶抑制剂的生物活性分泌。这将为 过渡到第2阶段，我们将在鼠遗传模型中建立安全性和功效。