Novel Strategies to Clear Bacteria from the CF Lung

清除 CF 肺细菌的新策略

• 批准号: 10751325
• 负责人: Saira Ahmad
• 金额: $ 9.47万
• 依托单位: ELDEC PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-24 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10751325
• 关键词: Acute; Affect; Award; Bacteria; Bacterial Infections; Birth; Blood; Businesses; Career Mobility; Cell membrane; Cells; Chronic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic Fibrosis sputum; Data; Dehydration; Development; Dose; Drug Kinetics; Genes; Genetic Diseases; Glosso-Sterandryl; Immune; Immune response; Immunocompromised Host; Inflammation; Inflammatory Response; Inhalation; Knowledge; Leukocyte Elastase; Liquid substance; Lung; Lung infections; Mentors; Modeling; Mucous body substance; Mus; Mutation; Nasal Epithelium; Neutrophilia; Nonsense Mutation; Normal Range; Palate; Patients; Peptide Hydrolases; Peptides; Peripheral; Pharmacologic Substance; Play; Predisposition; Protein Secretion; Pseudomonas aeruginosa; Pulmonary Cystic Fibrosis; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Inflammation; Rattus; Regulator Genes; Role; Staphylococcus aureus; Training; Work; chronic infection; cystic fibrosis airway; cystic fibrosis mouse; cystic fibrosis patients; cytokine; disease-causing mutation; drug development; experience; experimental study; improved; lung health; lung injury; neutrophil; novel; novel strategies; pathogen; peptidomimetics; pulmonary function

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. CF airways are immunocompromised and become colonized with bacteria soon after birth. Chronic bacterial infection leads to persistent and severe neutrophil-dominated pulmonary inflammation, high lung protease levels, lung damage and a decline in FEV1. CFTR modulator/correctors from Vertex increase CF patient lung function but do not bring it into the normal range, do not treat CF patients with nonsense mutations and for patients with pre-existing bacterial lung infections, do not clear bacteria from their lungs. Thus, there is a critical unmet need for novel, CFTR mutation-agnostic therapies to help clear bacteria from CF lungs and limit neutrophilic lung damage. Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1) is a secreted protein that is highly expressed in the lung, where it plays a key role in maintaining lung health. SPLUNC1 is a CF gene modifier, and patients with reduced SPLUNC1 levels have lower FEV1 and exacerbate more frequently. SPUNC1 inhibits Orai1, a ubiquitously expressed plasma membrane Ca2+ channel that regulates inflammation. However, SPLUNC1 is rapidly degraded by neutrophil elastase (NE), which we posit results in greater Orai1 activity and more inflammation. Consistent with this, our preliminary data indicate that Orai1 is upregulated in CF patient lung immune cells. Given Orai1’s proximal role in the immune response, Orai1 is thus an attractive target whose inhibition is predicted to help resolve CF inflammation. Eldec Pharma has developed a robust, novel peptidomimetic called ELD607, which reprises SPLUNC1’s ability to inhibit Orai1, yet is significantly more stable in the presence of NE, and significantly more potent/efficacious. ELD607 is stable in proteolytic CF sputum and inhibits Ca2+-influx in freshly-isolated CF patient peripheral neutrophils and in CF sputum-derived immune cells in a mutation-agnostic fashion. In murine lung infection models with common CF pathogens including P. aeruginosa and S. aureus, a single, inhaled dose of ELD607 reduced lung inflammation (neutrophilia, cytokines, NE) by 90%, decreased lung bacterial infection by 3-4 log10 CFUs and increased survival. In a chronic CF model (SCNN1B mice), ELD607 reduced neutrophilia and increased survival. These experiments demonstrate that rebalancing the lung’s inflammatory response by inhibiting Orai1 enhances the lungs’ natural ability to clear pathogens. In this proposal, we will use wild-type and rats to determine the pharmacokinetics of ELD607 after IV administration and determine its stability in blood. Secondly, we propose to evaluate whether acute and/or chronic administration of ELD607 reduce neutrophilia and /or clear bacteria from CF mice lungs. In terms of training and mentoring, this Diversity Supplement will allow Dr. Sassano to advance her knowledge in the drug development field, as well as permit her to acquire business and development experience to advance her career. Given her background, Dr. Sassano is an excellent candidate to improve diversity at Eldec Pharmaceuticals.

囊性纤维化（CF）是一种由囊性纤维化基因突变引起的遗传性疾病。 跨膜调节因子（CFTR）基因。CF气道免疫功能低下， 在出生后不久就被细菌占据。慢性细菌感染导致 持续性和重度嗜中性粒细胞为主的肺部炎症，高肺蛋白酶 水平，肺损伤和FEV 1下降。来自Vertex的CFTR调制器/校正器 增加CF患者的肺功能，但不使其进入正常范围，不治疗 无义突变CF患者和既存细菌性肺患者 感染，不能清除肺部的细菌。因此，有一个关键的未满足的需要， 新的CFTR突变不可知疗法，以帮助清除CF肺中的细菌， 嗜酸性肺损伤。短腭肺和鼻上皮克隆1（SPLUNC 1） 是一种在肺中高度表达的分泌蛋白，在肺中起关键作用， 保持肺部健康。SPLUNC 1是一种CF基因修饰剂， SPLUNC 1水平具有较低的FEV 1，并且更频繁地恶化。SPUNC 1抑制 Orai 1，一种普遍表达的质膜Ca 2+通道， 炎症然而，SPLUNC 1被中性粒细胞弹性蛋白酶（NE）迅速降解， 我们认为这会导致Orai 1活性更高，炎症更多。符合 因此，我们的初步数据表明，Orai 1在CF患者的肺免疫中上调， 细胞考虑到Orai 1在免疫应答中的近端作用，Orai 1因此是一个有吸引力的 其抑制作用预计有助于解决CF炎症。Eldec Pharma拥有 开发了一种名为ELD 607的强大的新型肽模拟物， 抑制Orai 1的能力，但在NE存在下显著更稳定， 更有效/更有效。ELD 607在蛋白水解CF痰液中稳定， 抑制新鲜分离的CF患者外周中性粒细胞和CF中的Ca 2+内流 以突变不可知的方式研究肿瘤衍生的免疫细胞。小鼠肺部感染 常见CF病原体包括铜绿假单胞菌和S. aureus，一个单一的， 吸入剂量的ELD 607通过以下方式减少肺部炎症（嗜中性粒细胞、细胞因子、NE）： 90%，减少肺部细菌感染3-4 log 10 CFU，并增加存活率。中 在慢性CF模型（SCNN 1B小鼠）中，ELD 607减少嗜中性粒细胞增多， 生存这些实验表明，重新平衡肺部的炎症 通过抑制Orai 1来增强肺部清除病原体的自然能力。在 本提案中，我们将使用野生型和大鼠来确定 ELD 607静脉给药后，并确定其在血液中的稳定性。其次我们 建议评估ELD 607的急性和/或慢性给药是否减少 嗜中性粒细胞和/或清除CF小鼠肺中的细菌。在培训和 指导，这种多样性补充将使萨萨诺博士，以提高她的知识 在药物开发领域，以及允许她获得业务， 发展经验，以促进她的职业生涯。考虑到她的背景，萨萨诺博士 是改善爱尔德克制药多样性的绝佳人选