Development of a Nematode-Derived Drug to Treat Asthma

开发线虫衍生药物来治疗哮喘

基本信息

批准号：
10602309
负责人：
Hung Nguyen
金额：
$ 25.9万
依托单位：
HOLOCLARA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602309
关键词：
Absenteeism at work Acute Adherence Adrenal Cortex Hormones Affect Allergens Allergic Allergic Disease American Animal Model Antiinflammatory Effect Area Asthma Autoimmune Diseases Biological Availability Biological Products Caregivers Cells Chronic Clinical Trials Complex Conduct Clinical Trials Consumption Development Disease Doctor of Philosophy Dose Drug usage Elements Eosinophilia Epithelial Cells Equilibrium Exposure to Foundations Funding Opportunities Goals Goblet Cells Health Care Costs Human Human Characteristics Hypersensitivity Immune response Immunity Immunotherapy Incidence Infection Inflammatory Inflammatory Bowel Diseases Injections Institution Insulin-Dependent Diabetes Mellitus Interleukin-10 Interleukin-13 Intraperitoneal Injections Investigational New Drug Application Licensing Lung Lymphoid Macrophage Maintenance Therapy Medical Care Costs Medical emergency Memory Metaplasia Modeling Mucous body substance Multiple Sclerosis Mus Natural Immunity Nematoda Nematode infections Nippostrongylus Oral Oral Administration Ovalbumin Pathogenicity Patients Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Population Production Publications Pulmonary Inflammation Pyroglyphidae Quality of life Regulation Research Research Personnel Respiratory Disease Safety Schools Severities Signal Transduction Small Business Innovation Research Grant Small Business Technology Transfer Research Smooth Muscle Myocytes Societies Sterility Study models Symptoms Technology Testing Therapeutic Time Toxic effect Translating United States National Institutes of Health adaptive immunity airway epithelium airway hyperresponsiveness airway remodeling asthma exacerbation asthma model asthmatic asthmatic patient clinically relevant compliance behavior cost cytokine drug maintenance economic cost immunoregulation improved insight interstitial manufacture medical attention meetings mortality mouse model novel pre-clinical prevent respiratory smooth muscle response side effect small molecule theories transcriptome

项目摘要

The current armamentarium of asthma drugs undoubtedly saves numerous lives every year but remains inadequate. It is estimated that up to 50% of all asthmatics are incompletely controlled, while the severe asthmatic population, despite being only 5% of all asthmatics, consumes ~50% of all asthma health care costs because drugs used in the management of their disease are relatively ineffective, expensive, and suffer from poor adherence. Accordingly, research that advances the discovery and development of new asthma drugs is a priority for numerous NIH institutions and reflected in numerous funding opportunities, including SBIR/STTR. Holoclara, Inc. is an early-stage pharmaceutical company, based upon a breakthrough discovery of roundworm- derived immunomodulatory, synthetic small molecules. Human clinical trials and animal model studies have found that roundworm infections alleviated inflammatory and autoimmune disease symptoms including those of asthma. We have discovered a novel small molecule, HC-C (Ascr#7), derived from roundworm extracts. HC-C can be synthesized, and our recent publication demonstrates intraperitoneal injection of HC-C prevents the development of asthma features in acute murine models of allergic lung inflammation. HC-C demonstrated a clear anti-inflammatory effect, suppressing the type 2 immune response by affecting both innate and adaptive immunity in these models. In this Phase 1 application we propose to establish the efficacy of oral delivery of HC- C in a chronic house dust mite (HDM) murine model of allergic lung inflammation (Aim 1), and further explore mechanism by testing the effects of HC-C on signaling and function of human airway smooth muscle (HASM) cells and human airway epithelial (HAE) cells in primary culture (Aim 2). Aim 1 will assess the dose-dependent effect of orally administered HC-C on HDM-induced lung inflammation, airway hyperresponsiveness, and airway remodeling. Aim 2 will assess the dose-dependent effect of HC-C on pro-contractile signaling and cellular contraction of HASM in cultures derived from asthmatic and nonasthmatic donors. HAE cultures, also derived from asthmatic and nonasthmatic donors, will be used to test the dose-dependent effect of HC-C on IL-13- induced cytokine, mucus production, and transcriptome regulation. Collectively, these studies will accomplish important preclinical goals, advancing proof-of-concept, and insight into mechanism, and justify the manufacturing of HC-C for Investigational New Drug Application (IND)-enabling non-clinical studies for filing an IND with the FDA.

目前的哮喘药物无疑每年挽救了无数人的生命，但仍然存在不足。据估计，高达 50% 的哮喘患者未得到完全控制，而严重的哮喘患者尽管哮喘人群仅占所有哮喘患者的 5%，但其消耗的医疗费用却占所有哮喘患者的约 50% 因为用于治疗疾病的药物相对无效、昂贵并且患有依从性差。因此，促进新哮喘药物的发现和开发的研究是一项众多 NIH 机构的优先事项，并反映在众多资助机会中，包括 SBIR/STTR。 Holocara, Inc. 是一家早期制药公司，基于蛔虫的突破性发现衍生的免疫调节、合成小分子。人体临床试验和动物模型研究发现蛔虫感染可以减轻炎症和自身免疫性疾病的症状，包括哮喘。我们发现了一种源自蛔虫提取物的新型小分子 HC-C (Ascr#7)。 HC-C 可以合成，我们最近的出版物表明腹腔注射 HC-C 可预防过敏性肺部炎症急性小鼠模型中哮喘特征的发展。 HC-C 展示了明显的抗炎作用，通过影响先天性和适应性来抑制2型免疫反应这些模型中的免疫力。在这一阶段 1 的应用中，我们建议确定口服 HC-的功效。 C 慢性屋尘螨 (HDM) 小鼠过敏性肺部炎症模型（目标 1），并进一步探索通过测试 HC-C 对人气道平滑肌 (HASM) 信号传导和功能的影响来了解机制原代培养中的细胞和人气道上皮 (HAE) 细胞（目标 2）。目标 1 将评估剂量依赖性口服 HC-C 对 HDM 诱导的肺部炎症、气道高反应性和气道的影响重塑。目标 2 将评估 HC-C 对促收缩信号传导和细胞的剂量依赖性影响来自哮喘和非哮喘供体的培养物中 HASM 的收缩。 HAE 培养物，也源自来自哮喘和非哮喘供体的样本将用于测试 HC-C 对 IL-13 的剂量依赖性影响诱导细胞因子、粘液产生和转录组调节。总的来说，这些研究将完成重要的临床前目标、推进概念验证和对机制的洞察，并证明制造用于新药研究申请 (IND) 的 HC-C，以便进行非临床研究以提交申请与 FDA 进行 IND 申请。