Inhalation Repurposing of An Approved Drug to Treat Severe Asthma

项目摘要 永旺帝国的业务目标和这个SBIR项目的目的是执行KEY 将氯硝柳胺作为新的哮喘治疗方法的步骤。治疗理论基础 因为这些研究是基于氯硝柳胺抑制离子通道的初步发现 对呼吸道平滑肌收缩和粘蛋白高分泌起关键作用。这两个都是 病理过程会导致呼吸道狭窄，除了 炎症，作为哮喘的核心特征。现有药物不能充分缓解 更严重的治疗难治性患者的气道狭窄。特别是，它的功效 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。 TMEM16A是一种钙激活的氯离子通道，调节钙信号转导。 呼吸道和呼吸道平滑肌收缩所必需的。氯硝柳胺是FDA批准的 口服药物最初是在几十年前发现的，并被安全地用作抗蠕虫。那是最近的事 在高通量无偏筛选中鉴定为特定的TMEM16A抑制剂。氯硝柳胺 通过这种机制完全松弛收缩的呼吸道，并抵抗脱敏途径 削弱了β-受体激动剂的有效性。它还可以减少哮喘引起的粘蛋白释放- 关联的激活信号。因此，改变用途的氯硝柳胺对TMEM16A的抑制是一种 有吸引力的哮喘治疗新方法，并将受益于该药物的已建立的人类 安全记录。然而，氯硝柳胺的生物利用度很低，不太可能达到TMEM16A 通过口服给药在呼吸道内。该项目的第一个目标是重新配制氯硝柳胺 通过粒子工程使吸入剂量成为可能。下一个目标是使用新的 吸入性研究中的配方，以确认药物达到局部目标并将打开 航空公司被一种收缩因子激怒了。更多的研究将确定药物动力学 和吸入性氯硝柳胺的初步毒理学特征。这些研究对于检验 科学假设，在呼吸道中抑制TMEM16A是安全有效的治疗方法 打开阻塞的呼吸道。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，申请IND并进行人体试验。

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.