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：
10680454
负责人：
Saira Ahmad
金额：
$ 97.78万
依托单位：
ELDEC PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-10 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10680454
关键词：
Aerosols Affect Alveolar Macrophages Antibiotic Resistance Antimicrobial Effect Bacteria Bacterial Antibiotic Resistance Bacterial Infections Biological Models Birth Burkholderia cepacia Burkholderia cepacia complex Capital Cell membrane Cells Chronic Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Cystic Fibrosis sputum Data Dehydration Disease Progression Dose Drug Kinetics Effector Cell Equilibrium Ferrets Foundations Genes Genetic Diseases Glosso-Sterandryl Haemophilus influenzae Immune Immune response Immunocompromised Host Immunology Immunomodulators Inflammation Inflammatory Response Inhalation Iowa Leukocyte Elastase Lung Lung diseases Lung infections Mediating Modeling Mucous body substance Mus Mutation Nasal Epithelium Nebulizer Neutrophilia Nonsense Mutation Normal Range Palate Patients Peptide Hydrolases Peptides Peripheral Play Population Privatization Protein Secretion Proteins Pseudomonas Pseudomonas aeruginosa Public Health Pulmonary Cystic Fibrosis Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary Inflammation Reagent Regimen Regulator Genes Role Sodium Chloride Staphylococcus aureus System Testing Therapeutic Translating Universities Water aerosolized antimicrobial cell type chronic infection clinical development combat cystic fibrosis airway cystic fibrosis infection cystic fibrosis mouse cystic fibrosis patients cytokine disease-causing mutation experimental study improved lung health lung injury methicillin resistant Staphylococcus aureus multidrug-resistant Pseudomonas aeruginosa neutrophil novel novel strategies pathogen peptidomimetics prevent programs 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 such as TRIKAFTA significantly increase CF patient lung function by >10% but do not bring it into the normal range and for patients with pre-existing bacterial lung infections, do not clear bacteria from their lungs. Moreover, these compounds do not treat CF patients with nonsense mutations where no CFTR protein is produced. 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. Orai1 is a ubiquitously expressed plasma membrane Ca2+ channel that regulates inflammation. We found that SPLUNC1 inhibits Orai1. 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 CF mice to understand which immune effector cells are regulated by ELD607. The CF ferret model developed by Dr Engelhardt and coworkers at the University of Iowa spontaneously develops chronic CF lung disease including inflammation and bacterial infection. We will first validate that we can deliver sufficient doses of ELD607 via nebulizer to safely inhibit Orai1 in wild-type and CF ferret lungs. Then we will chronically administer ELD607 to CF ferrets with existing lung disease in order to study the impact of ELD607 on CF disease progression.

囊性纤维化（CF）是一种由囊性纤维化跨膜调节因子突变引起的遗传性疾病 (CFTR) 基因。 CF 气道免疫功能低下，出生后不久就会被细菌定植。慢性细菌感染导致持续且严重的中性粒细胞为主的肺部炎症，高 Vertex 的肺蛋白酶水平、肺损伤和 FEV1 调节剂/校正剂下降。 TRIKAFTA 显着使 CF 患者肺功能增加 >10%，但未使其恢复到正常范围，并且对于已有细菌性肺部感染的患者，不要清除肺部的细菌。化合物不能治疗具有不产生CFTR蛋白的无义突变的CF患者。是对新颖的 CFTR 突变不可知疗法的一个关键的未满足需求，以帮助清除 CF 肺部和限制中性粒细胞性肺损伤。短腭肺和鼻上皮克隆 1 (SPLUNC1) 是一种分泌蛋白。 SPLUNC1 是一种 CF 基因，在肺部高度表达，在维持肺部健康方面发挥着关键作用。 SPLUNC1 水平降低的患者的 FEV1 较低且 Orai1 恶化的频率更高。我们发现 SPLUNC1 是一种普遍表达的质膜 Ca2+ 通道，可调节炎症。抑制 Orai1。然而，SPLUNC1 会被中性粒细胞弹性蛋白酶 (NE) 快速降解，我们推测其结果是与此相一致的是，Orai1 活性更高，炎症也更多。我们的初步数据表明，Orai1 是鉴于 Orai1 在免疫反应中的近端作用，Orai1 在 CF 患者肺免疫细胞中表达上调。 Eldec Pharma 开发出了一个有吸引力的靶点，其抑制作用预计有助于解决 CF 炎症。一种名为 ELD607 的强大新型肽模拟物，它重现了 SPLUNC1 抑制 Orai1 的能力，但在 NE 存在下显着更稳定，并且 ELD607 在 NE 存在下显着更稳定。蛋白水解 CF 痰，并抑制新鲜分离的 CF 患者外周中性粒细胞和 CF 中的 Ca2+ 内流在具有常见 CF 的小鼠肺部感染模型中，痰衍生的免疫细胞以与突变无关的方式进行。包括铜绿假单胞菌和金黄色葡萄球菌在内的病原体，单次吸入剂量的 ELD607 可减轻肺部炎症（中性粒细胞、细胞因子、NE）减少 90%，肺部细菌感染减少 3-4 log10 CFU，并增加在慢性 CF 模型（SCNN1B 小鼠）中，ELD607 减少了中性粒细胞增多并提高了存活率。实验表明，通过抑制 Orai1 来重新平衡肺部的炎症反应可以增强在本提案中，我们将使用野生型和 CF 小鼠来了解肺部清除病原体的天然能力。 Engelhardt 博士及其同事开发的 CF 雪貂模型受 ELD607 调节。爱荷华大学的一名患者自发患上慢性 CF 肺病，包括炎症和细菌我们将首先验证我们可以通过雾化器提供足够剂量的 ELD607 以安全地抑制 Orai1。然后，我们将长期向具有现有肺的 CF 雪貂施用 ELD607。疾病以研究 ELD607 对 CF 疾病进展的影响。