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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.

项目总结