Airway Alkalinization and Repurposing Tromethamine as a Therapeutic Approach in Cystic Fibrosis

气道碱化和重新利用氨丁三醇作为囊性纤维化的治疗方法

• 批准号: 9289053
• 负责人: DAVID A STOLTZ
• 金额: $ 107.03万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-10 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9289053
• 关键词: Affect; Age; Alkalinization; Animals; Bicarbonates; Birth; Buffers; Chronic; Clinical; Clinical Research; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Development; Disease; Duct (organ) structure; Early Intervention; FDA approved; Failure; Family suidae; Genes; Gland; Goals; Hereditary Disease; Host Defense; Host Defense Mechanism; Hour; Human; Impairment; Infection; Inflammation; Knowledge; Lead; Life; Lung; Lung diseases; Mediating; Metabolic acidosis; Mucociliary Clearance; Mucous body substance; Mutation; Newborn Infant; Pathogenesis; Pharmaceutical Preparations; Positioning Attribute; Property; Publishing; Pulmonary Cystic Fibrosis; Recurrence; Respiratory Failure; Rheology; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; Tris-A; Tromethamine; Viscosity; Work; aerosolized; airway surface liquid; alkalinity; antimicrobial; base; clinical development; cystic fibrosis airway; early cystic fibrosis; improved; infancy; killings; new therapeutic target; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; restoration; screening; therapeutic development; therapeutic target

PROJECT SUMMARY Despite the development of new therapies, cystic fibrosis (CF) remains a life-shortening disease. Airway infec- tion and inflammation begin during infancy and lead to respiratory failure. Thus, early interventions aimed at correcting the initial host defense defects and preventing/reducing infection could dramatically improve the course of CF lung disease. It is well known that mutations in the gene encoding CFTR, a HCO – and Cl– con- 3 ducting channel, cause CF. Yet, the origins of CF lung disease have remained less well understood. We dis- covered that loss of CFTR impairs two important airway host defense mechanisms. a) Reduced activity of air- way surface liquid (ASL) antimicrobials. b) More viscous mucus that also has abnormal properties, impairing its ability to detach from submucosal gland ducts, thus hindering mucociliary transport (MCT). In both cases, loss of CFTR-mediated HCO3– secretion and an abnormally acidic pH are key factors. Our long-term goal is to develop novel therapeutics that target primary host defense defects due to loss of CFTR function. The overall objective of this proposal is to determine if airway alkalinization, with a repurposed drug, can prevent or allevi- ate the development of CF airway disease. Our hypothesis is that airway alkalinization with tromethamine (THAM, an FDA-approved alkalinizing agent in human clinical use for metabolic acidosis), will restore airway host defenses in CF and prevent/alleviate the development of CF airway disease. We found in humans and pigs that aerosolized THAM, a tris-based, non-bicarbonate buffer, causes a sustained increase in ASL pH and the effect lasts for hours, in contrast to a much shorter duration with NaHCO3. THAM enhanced ASL bacterial killing and decreased mucus viscosity. We test the following Specific Aims: Aim 1. Does aerosolized THAM produce a prolonged increase in ASL pH and enhance antimicrobial activity in pigs and humans? Based upon our published and unpublished data, our working hypothesis is that aerosolized THAM will increase ASL pH and restore ASL antimicrobial properties, in humans and pigs with CF. Aim 2. Will airway alkalinization im- prove MCT? From our earlier studies, we postulate that airway alkalinization with THAM will reverse MCT de- fects in CF, thereby enhancing MCT in CF. Aim 3. Does airway alkalinization alleviate or prevent early airway disease in CF pigs? Our published and preliminary data show that CF pigs already have airway host defense defects present at birth and develop airway disease within 3 weeks of age. Thus, we hypothesize that, in CF pigs, long-term restoration of ASL pH with THAM will improve airway host defense and lessen or prevent early airway disease in CF pigs. We are uniquely positioned to translate our recent discoveries on the pathogenesis of CF lung disease into a therapeutic intervention. These results, from both human and preclinical animal stud- ies, will be transformative for CF and likely other airway diseases. They will have an important positive impact on accelerating clinical development of THAM and other new therapeutic interventions and endpoints for early CF, a critically important time point in the era of universal newborn CF screening.

项目概要 尽管开发了新疗法，囊性纤维化（CF）仍然是一种缩短寿命的疾病。气道感染 炎症和炎症在婴儿期开始并导致呼吸衰竭。因此，早期干预旨在 纠正最初的宿主防御缺陷并预防/减少感染可以显着改善 CF肺部疾病的病程。众所周知，编码 CFTR（一种 HCO - 和 Cl -）的基因发生突变， 3 管道通道，导致CF。然而，人们对 CF 肺病的起源仍知之甚少。我们dis- 报道称 CFTR 的缺失会损害两种重要的气道宿主防御机制。 a) 空气活动减少- 方式表面液体（ASL）抗菌剂。 b) 更粘稠的粘液也具有异常特性，损害 它能够与粘膜下腺管分离，从而阻碍粘液纤毛运输（MCT）。在这两种情况下， CFTR 介导的 HCO3 分泌丧失和 pH 值异常酸性是关键因素。我们的长期目标是 开发针对由于 CFTR 功能丧失而导致的主要宿主防御缺陷的新疗法。整体 该提案的目的是确定使用重新调整用途的药物进行气道碱化是否可以预防或缓解 CF气道疾病的发展。我们的假设是氨丁三醇碱化气道 （THAM，FDA 批准的人类临床用于治疗代谢性酸中毒的碱化剂），将恢复气道 CF 宿主防御并预防/减轻 CF 气道疾病的发展。我们在人类中发现 雾化 THAM（一种基于三羟甲基氨基甲烷的非碳酸氢盐缓冲液）的猪会导致 ASL pH 值持续升高， 该效果可持续数小时，而 NaHCO3 的持续时间要短得多。 THAM 增强 ASL 细菌 杀灭并降低粘液粘度。我们测试以下具体目标： 目标 1. 雾化 THAM 吗 导致 ASL pH 值长期升高并增强猪和人类的抗菌活性？基于 根据我们已发表和未发表的数据，我们的工作假设是雾化 THAM 会增加 ASL pH 值 并恢复患有 CF 的人和猪的 ASL 抗菌特性。目标 2. 气道碱化是否会发生？ 证明MCT？根据我们早期的研究，我们假设 THAM 气道碱化将逆转 MCT 去- 感染 CF，从而增强 CF 中的 MCT。目标 3. 气道碱化能否缓解或预防早期气道 CF猪的疾病？我们公布的初步数据表明，CF猪已经具有气道宿主防御能力 出生时就存在缺陷，并在 3 周内出现气道疾病。因此，我们假设，在 CF 猪，用 THAM 长期恢复 ASL pH 将改善呼吸道宿主防御并减少或预防早期 CF 猪的气道疾病。我们处于独特的地位，可以转化我们关于发病机制的最新发现 将 CF 肺部疾病纳入治疗干预。这些结果来自人类和临床前动物研究 ies，将对 CF 和可能的其他气道疾病产生革命性的影响。他们将产生重要的积极影响 关于加速 THAM 和其他新的治疗干预措施和早期终点的临床开发 CF，全民新生儿CF筛查时代的一个至关重要的时间点。