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: 9918957
• 负责人: DAVID A STOLTZ
• 金额: $ 105.46万
• 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/9918957
• 关键词: Affect; Age; Airway Disease; 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; Genetic Diseases; Gland; Goals; 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; 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; injured airway; new therapeutic target; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; recurrent infection; 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.

项目摘要 尽管有新疗法的发展，但囊性纤维化（CF）仍然是一种寿命差的疾病。气道信息 在婴儿期开始开始和炎症，导致呼吸衰竭。那是针对的早期干预措施 纠正最初的宿主防御缺陷并防止/减少感染可能会大大改善 CF肺部病的过程。众所周知，编码CFTR的基因中的突变，HCO - 和Cl- con- 3 导管通道，原因参见。然而，CF肺部疾病的起源知之甚少。我们不 涵盖了CFTR的损失会损害两种重要的气道托管防御机制。 a）空气活性减少 表面液体（ASL）抗菌剂。 b）更多粘性粘液也具有异常性能，损害 它从粘膜粘膜导管中脱离的能力，从而阻碍粘膜纤毛运输（MCT）。在这两种情况下， CFTR介导的HCO3 - 分泌和绝对酸性pH的丧失是关键因素。我们的长期目标是 由于CFTR功能的丧失，开发了针对主要宿主防御缺陷的新型治疗。总体 该提案的目的是确定气道碱化是否使用重新利用的药物可以预防或减轻 在CF气道疾病的发展中。我们的假设是用葡萄胺的气道碱化 （Tham，一种由FDA批准的人类临床用途用于代谢性酸中毒的碱化剂），将恢复气道 CF中的宿主防御措施并预防/减轻CF气道疾病的发展。我们在人类中发现 雾化Tham的猪是一种基于Tris的非双碳酸盐缓冲液，导致ASL pH和 效果持续数小时，与Nahco3持续时间短得多。 Tham增强了ASL细菌 杀死和改善粘液粘度。我们测试以下特定目的：目标1。 在猪和人类中会长期增加ASL pH并增强抗菌活性？基于 我们已发布且未发表的数据，我们的工作假设是雾化的THAM将增加ASL pH 并恢复具有CF的人类和猪的ASL抗菌特性。目标2。 证明MCT？从我们较早的研究中，我们推测，用THAM的气道碱化将逆转MCT CF中的事实，从而增强了CF中的MCT。目标3。气道碱化减轻或防止早期气道 CF猪的疾病？我们已发布的初步数据表明，CF猪已经有气道主机防御 出生时出现的缺陷，并在3周龄内发展出气道疾病。那我们假设在CF中 猪，长期用THAM恢复ASL pH将改善气道宿主防御，并减轻或预防早期 CF猪中的气道疾病。我们在转化有关发病机理的最新发现方面是独特的位置 CF肺部疾病的治疗干预措施。这些结果，来自人类和临床前动物螺柱 IES，对于CF以及可能的其他气道疾病将是变革性的。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的临床开发以及早期的终点 CF，这是通用新生儿CF筛查时代至关重要的时间点。