Development of a Nematode-Derived Drug to Treat Asthma

目前的哮喘药物药库每年无疑挽救了无数人的生命，但仍然 不够充分。据估计，多达50%的哮喘患者没有得到完全控制，而严重的 哮喘人口虽然只占所有哮喘患者的5%，但却消耗了所有哮喘医疗保健费用的50%左右 因为用于治疗他们疾病的药物相对无效，价格昂贵，并受到 忠诚度不高。因此，推动发现和开发新的哮喘药物的研究是一项 这是许多国立卫生研究院机构的优先事项，并反映在许多供资机会中，包括SBIR/STTR。 Holoclara，Inc.是一家早期制药公司，基于对蛔虫的突破性发现- 衍生的具有免疫调节作用的合成小分子。人类临床试验和动物模型研究已经 研究发现，蛔虫感染可以缓解炎症和自身免疫性疾病的症状，包括 哮喘。我们从蛔虫提取物中发现了一种新的小分子，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可以预防 急性过敏性肺炎小鼠模型中哮喘特征的发展。HC-C演示了一个 明确的抗炎作用，通过影响先天和获得性来抑制2型免疫反应 在这些型号中有豁免权。在这个第一阶段的应用中，我们建议建立口服HC- C在慢性屋尘螨(HDM)小鼠过敏性肺部炎症模型中的作用(目标1)，并进一步探讨 HC-C对人气道平滑肌(HASM)信号和功能影响的机制研究 原代培养中的细胞和人呼吸道上皮(HAE)细胞(目标2)。目标1将评估剂量依赖关系 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 改建。目的2将评估HC-C对促收缩信号和细胞的剂量依赖效应 哮喘和非哮喘供者培养中HASM的收缩。Hae培养，也衍生出 将用于检测HC-C对IL-13的剂量依赖效应。 诱导细胞因子、粘液产生和转录组调节。总而言之，这些研究将实现 重要的临床前目标、推进概念验证和对机制的洞察，并证明 制造用于研究新药申请(IND)的HC-C-使非临床研究能够提交 与美国食品和药物管理局合作。

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.