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: 10541898
• 负责人: John Sullivan
• 金额: $ 99.28万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541898
• 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; Dryness; 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; Relaxation; 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; bronchial epithelium; burden of illness; capsule; chemical property; constriction; cytokine; desensitization; disease phenotype; drug candidate; drug repurposing; helminth infection; high throughput screening; improved; in vivo; inhibitor; liquid chromatography mass spectrometry; methacholine; mouse model; mucin hypersecretion; muscle form; novel strategies; novel therapeutic intervention; novel therapeutics; particle; pharmacokinetics and pharmacodynamics; pre-Investigational New Drug meeting; 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 Respire的业务目标和SBIR项目的目的是执行关键的 将氯硝柳胺作为一种新的哮喘治疗方法。治疗原理 这些研究的基础是初步发现，氯硝柳胺抑制离子通道， 对于气道平滑肌收缩和粘蛋白高分泌至关重要。这两 病理过程有助于气道狭窄，并且被认为除了 炎症是哮喘的核心特征。现有药物无法充分缓解 气道狭窄更严重，治疗难治性患者。特别是， 吸入的β-激动剂在细胞水平上受到重复使用脱敏和 炎症的间接影响。因此，需要新的治疗方法。 TMEM 16 A是钙激活的氯离子通道，其调节细胞中的钙信号传导。 是气道平滑肌收缩所必需的。氯硝柳胺是FDA批准的 几十年前首次发现的口服药物，安全地用作抗蠕虫药。最近有 在高通量无偏筛选中鉴定为特异性TMEM 16 A抑制剂。柳胺 通过这种机制完全放松收缩的气道，并抵抗脱敏途径， 会削弱β-受体激动剂的效果它还能减少哮喘引起的粘蛋白释放- 相关的激活信号。因此，用改变用途的氯硝柳胺抑制TMEM 16 A是一种有效的方法。 有吸引力的新的哮喘治疗方法，并将受益于药物的既定人类 安全记录。然而，氯硝柳胺的生物利用度较差，不太可能达到TMEM 16 A 在呼吸道中通过口服给药。该项目的第一个目标是重新制定氯硝柳胺 通过粒子工程来实现吸入剂量。下一个目标是使用新的 吸入研究中的制剂，以确认药物局部达到其目标， 呼吸道受到收缩剂的刺激其他研究将确定药代动力学 和吸入氯硝柳胺的初始毒理学特征。这些研究对于测试 科学假设，抑制气道中的TMEM 16 A是一种安全有效的方法， 开放阻塞的气道。它们也代表了移动项目所需的重要步骤 更接近与FDA的讨论，提交IND并在人体研究中进行测试。