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

• 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
• 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

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.

项目摘要 AEON呼吸的业务目标以及该SBIR项目的目的是执行密钥 重新利用烟酰胺作为一种新的哮喘治疗的步骤。治疗原理 对于这些研究，基于初始发现，即烟酰胺抑制了一个离子通道 气道平滑肌收缩和粘蛋白突出分泌的关键。这两个 病理过程导致气道狭窄，并考虑到 炎症，作为哮喘的核心特征。现有药物无法充分营救 气道在更严重的治疗难治性患者中变窄。特别是 通过重复使用脱敏和 炎症的间接影响。因此，需要采用新的治疗方法。 TMEM16A是一种钙活化的氯化物通道，可调节钙信号传导 气道是平滑肌收缩所必需的。烟酰胺是FDA批准的 口服药物最初是几十年前发现的，并安全地用作抗螺旋。最近是 在高吞吐量公正屏幕中鉴定为特定的TMEM16A抑制剂。烟酰胺 通过这种机制完全放松签约的气道，并抵制脱敏途径 破坏了β激动剂的有效性。它还减少了哮喘诱导的粘蛋白释放 相关的激活信号。因此 有吸引力的新哮喘治疗方法，将受益于该药物已建立的人 安全记录。但是，烟酰胺的生物利用度较差，不太可能达到TMEM16A 在呼吸道中通过口服给药。该项目的第一个目的是重新重新制定烟酰胺 通过粒子工程以实现内部剂量。下一个目标是使用新的目标 吸入研究中的公式以确认该药物在本地达到其靶标，并将打开 Airways由收缩代理引起。其他研究将建立药代动力学 以及遗传烟酰胺的初始毒理学特征。这些研究对于测试 科学的假设是，在气道中抑制TMEM16A是一种安全有效的方法 开放的阻塞气道。它们还代表着移动项目所需的重要步骤 更接近与FDA的讨论，在人类研究中提交IND和测试。