Inhalation Repurposing of An Approved Drug to Treat Severe Asthma

吸入再利用已批准药物治疗严重哮喘

基本信息

批准号：
10395854
负责人：
John Sullivan
金额：
$ 119.31万
依托单位：
AEON RESPIRE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-09 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395854
关键词：
Adrenal Cortex Hormones Agonist Allergic Animals Asthma Autopsy Biological Availability Biological Markers Biological Products Bronchodilation Businesses Calcium Calcium Channel Blockers Calcium Signaling Canis familiaris Chloride Channels Clinical Clinical Pathology Clinical Trials Contracts Data Disease Dose Drug Kinetics Effectiveness Engineering Epithelial Cells Extrinsic asthma FDA approved Formulation Goals Half-Life Helminths Human Inflammation Inflammatory Inhalation Inhalation Toxicology Inhalators Ion Channel Lung Measures Mucins Mucous body substance Muscle Contraction Oral Particle Size Pathologic Processes Pathway interactions Patient Selection Patients Persons Pharmaceutical Preparations Phase Plasma Positioning Attribute Powder dose form Precipitation Process Production Property Rattus Refractory Risk-Benefit Assessment Route Safety Signal Transduction Small Business Innovation Research Grant Smooth Muscle Technology Testing Therapeutic Tissues Toxicokinetics Toxicology airway hyperresponsiveness airway inflammation airway obstruction base bronchial epithelium burden of illness capsule chemical property cytokine desensitization disease phenotype drug candidate drug repurposing helminth infection high throughput screening in vivo inhibitor liquid chromatography mass spectrometry meetings methacholine mouse model mucin hypersecretion muscle form novel strategies novel therapeutics particle pharmacokinetics and pharmacodynamics pulmonary function respiratory smooth muscle therapeutic evaluation

项目摘要

Project Summary The business objective of Aeon Respire, and the purpose of this SBIR Project, is to execute key steps towards repurposing niclosamide as a new asthma treatment. The therapeutic rationale for these studies is based on initial findings that niclosamide inhibits an ion channel that is pivotal for airway smooth muscle contraction and mucin hypersecretion. Both of these pathologic processes contribute to airway narrowing and are considered, in addition to inflammation, as the core features of asthma. Existing medications fail to adequately relieve airway narrowing in more severe, treatment refractory patients. In particular, the efficacy of inhaled beta-agonists is compromised at a cellular level by both repeat use desensitization and the indirect effects of inflammation. Therefore, there is need for new treatment approaches. TMEM16A is a calcium-activated chloride channel that regulates calcium signaling in the airways and is required for airway smooth muscle contraction. Niclosamide is an FDA-approved oral drug originally discovered decades ago and safely used as an anti-helminth. It was recently identified in a high throughput unbiased screen as a specific TMEM16A inhibitor. Niclosamide fully relaxes contracted airways via this mechanism and resists desensitization pathways that undermine the effectiveness of beta-agonists. It also reduces mucin release induced by asthma- associated activation signals. TMEM16A inhibition with repurposed niclosamide is therefore an attractive new asthma treatment approach and will benefit from the drug’s established human safety record. Niclosamide, however, has poor bioavailability and is unlikely to reach TMEM16A in the airways through oral dosing. The first objective of the project is to reformulate niclosamide through particle engineering to enable inhaled dosing. The next objective is to use the new formulation in inhalation studies to confirm the drug reaches its target locally and will open airways provoked by a contractile agent. Additional studies will establish the pharmacokinetic and initial toxicologic profile of inhaled niclosamide. These studies are crucial to test the scientific hypothesis that inhibiting TMEM16A in the airways is a safe and effective approach to open obstructed airways. They also represent important steps required to move the project closer to discussions with the FDA, filing an IND and testing in human studies.

项目概要 Aeon Respire 的业务目标以及该 SBIR 项目的目的是执行关键将氯硝柳胺重新用作新的哮喘治疗方法的步骤。这些研究基于氯硝柳胺抑制离子通道的初步发现对气道平滑肌收缩和粘蛋白分泌过多至关重要。除了以下因素之外，病理过程也会导致气道变窄并被考虑：炎症作为哮喘的核心特征，无法充分缓解。对气道狭窄较严重、治疗难治的患者疗效尤其显着。重复使用脱敏和重复使用会在细胞水平上损害吸入的β受体激动剂因此，需要新的治疗方法。 TMEM16A 是一种钙激活的氯离子通道，可调节钙信号传导气道，是气道平滑肌收缩所必需的，氯硝柳胺是 FDA 批准的一种药物。口服药物最初是几十年前发现的，最近才被安全地用作抗蠕虫药。在高通量无偏筛选中被鉴定为特定的 TMEM16A 抑制剂。通过这种机制充分放松收缩的气道并抵抗脱敏途径破坏β受体激动剂的有效性，它还能减少哮喘引起的粘蛋白释放。因此，重新调整氯硝柳胺的 TMEM16A 抑制作用是一种有效的方法。有吸引力的新哮喘治疗方法，并将受益于该药物已建立的人体然而，氯硝柳胺的安全记录较差，不太可能达到 TMEM16A。该项目的首要目标是重新配制氯硝柳胺。通过粒子工程实现吸入给药下一个目标是使用新的方法。吸入研究中的配方，以确认药物在局部达到其目标并会打开进一步的研究将确定由收缩剂引起的气道的药代动力学。这些研究对于测试吸入氯硝柳胺的初始毒理学特征至关重要。科学假设抑制气道中的 TMEM16A 是一种安全有效的方法它们还代表了移动该项目所需的重要步骤。与 FDA 进行更密切的讨论，提交 IND 并进行人体研究测试。