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.

囊性纤维化是一种由囊性纤维化基因突变引起的遗传病。 跨膜调节因子(CFTR)基因。Cf呼吸道免疫功能受损， 在出生后不久就被细菌侵占。慢性细菌感染导致 持续和严重的中性粒细胞主导的肺部炎症，高肺蛋白水解酶 水平、肺损伤和FEV1下降。来自顶点的CFTR调制器/校正器 增加慢性阻塞性肺疾病患者肺功能但未使其恢复正常，不予治疗 Cf无义突变患者和先前存在细菌肺的患者 感染，并不能清除肺部的细菌。因此，存在着严重的未得到满足的需求 新型CFTR突变不可知疗法有助于清除肺组织中的细菌并限制 中性粒细胞肺损伤。短腭肺和鼻上皮克隆1(SPLunc1) 是一种分泌蛋白，在肺中高度表达，在肺中发挥关键作用 保持肺部健康。SPLunc1是一种CF基因修饰物，患者 SPLunc1水平较低，FEV1加重较频繁。SPunc1抑制 ORAI1，一种普遍表达的质膜钙通道，调节 发炎。然而，SPLunc1被中性粒细胞弹性蛋白酶(NE)迅速降解， 我们认为这会导致更多的Orai1活性和更多的炎症。与一致 我们的初步数据表明，Orai1在CF患者的肺免疫中上调 细胞。鉴于Orai1的S在免疫反应中的近端作用，Orai1因此是一个有吸引力的 其抑制作用被预测为有助于缓解CF炎症的靶点。Eldec Pharma已经 开发了一种名为ELD607的强健、新颖的模拟肽药物，这让SPLUN1的S感到意外 抑制Orai1的能力，但在NE存在下显著更稳定，以及 明显更有效/更有效。ELD607在蛋白水解性CF痰中稳定， 抑制新鲜分离的CF患者外周血中性粒细胞和CF中的钙离子内流 以一种突变不可知的方式检测来自痰的免疫细胞。在小鼠肺部感染中 包括铜绿假单胞菌和金黄色葡萄球菌在内的常见CF病原体的模型， 吸入剂量的ELD607通过以下方式减少肺部炎症(中性粒细胞、细胞因子、NE) 90%，减少肺部细菌感染3-4log10CFU，提高存活率。在一个 慢性CF模型(SCNN1B小鼠)，ELD607降低中性粒细胞并增加 生死存亡。这些实验表明，重新平衡肺部的炎症 通过抑制Orai1的反应增强了肺部清除病原体的自然能力。在……里面 本提案中，我们将使用野生型和大鼠来测定其药代动力学。 ELD607静脉给药后测定其在血液中的稳定性。其次，我们 建议评估急性和/或慢性服用ELD607是否会降低 中性粒细胞和/或CF小鼠肺部的清除细菌。在培训和培训方面 指导，这一多样性补充将允许Sassano博士推进她的知识 在药物开发领域，以及允许她收购业务和 发展经验，以推进她的职业生涯。考虑到她的背景，萨萨诺博士 这是Eldec制药公司提高多样性的优秀候选人。