Novel Strategies to Clear Bacteria from the CF Lung

清除 CF 肺细菌的新策略

基本信息

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
项目类别：
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

项目摘要

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突变引起的遗传性疾病 CF 气道免疫功能低下，并且存在跨膜调节基因 (CFTR)。出生后不久就被细菌定植，导致慢性细菌感染。持续且严重的中性粒细胞为主的肺部炎症，高肺蛋白酶 Vertex 的 CFTR 调节器/校正器水平、肺损伤和 FEV1 下降。增加CF患者肺功能但未使其进入正常范围，不治疗具有无义突变的 CF 患者和先前存在细菌性肺的患者感染，不能清除肺部的细菌，因此，对细菌的需求亟待满足。新颖的 CFTR 突变不可知疗法可帮助清除 CF 肺部的细菌并限制中性粒细胞性肺损伤。短腭肺和鼻上皮克隆 1 (SPLUNC1) 是一种在肺部高度表达的分泌蛋白，在肺部发挥着关键作用 SPLUNC1 是一种 CF 基因修饰剂，可减少患者的肺部健康。 SPLUNC1 水平具有较低的 FEV1 且 SPUNC1 抑制更频繁地恶化。 Orai1，一种普遍表达的质膜 Ca2+ 通道，可调节然而，SPLUNC1 会被中性粒细胞弹性蛋白酶 (NE) 迅速降解，我们认为这导致了更大的 Orai1 活性和更多的炎症。我们的初步数据表明 Orai1 在 CF 患者肺部免疫中表达上调鉴于 Orai1 在免疫反应中的近端作用，Orai1 因此是一个有吸引力的细胞。 Eldec Pharma 的抑制作用预计有助于解决 CF 炎症。开发了一种强大的新型肽模拟物 ELD607，它重复了 SPLUNC1 抑制 Orai1 的能力，但在 NE 存在的情况下明显更稳定，并且 ELD607 在蛋白水解 CF 痰中更有效/更稳定。抑制新鲜分离的 CF 患者外周中性粒细胞和 CF 中的 Ca2+ 内流在小鼠肺部感染中，痰源性免疫细胞以突变不可知的方式进行。常见 CF 病原体的模型，包括铜绿假单胞菌和金黄色葡萄球菌，吸入剂量的 ELD607 可减少肺部炎症（中性粒细胞增多、细胞因子、NE） 90%，肺部细菌感染减少 3-4 log10 CFU，并提高存活率。慢性 CF 模型（SCNN1B 小鼠），ELD607 减少中性粒细胞并增加这些实验表明，重新平衡肺部的炎症。通过抑制 Orai1 来增强肺部清除病原体的自然能力。在这个建议中，我们将使用野生型和大鼠来确定其药代动力学 ELD607静脉注射后并测定其在血液中的稳定性。建议评估 ELD607 的急性和/或慢性给药是否会减少中性粒细胞增多症和/或清除 CF 小鼠肺部的细菌。在指导下，这份多样性补充品将使萨萨诺博士能够提高她的知识在药物开发领域，以及允许她收购业务和鉴于她的背景，萨萨诺博士有能力发展自己的职业生涯。是改善 Eldec Pharmaceuticals 多元化的优秀候选人。