Development of a Nematode-Derived Drug to Treat Asthma

目前的哮喘药物设备每年无疑挽救了许多生命，但仍然存在 不足据估计，高达50%的所有哮喘患者没有得到完全控制，而严重的哮喘患者没有得到完全控制。 哮喘人群，尽管只占所有哮喘患者的5%，却消耗了所有哮喘医疗保健费用的50% 因为用于治疗他们疾病的药物相对无效、昂贵， 坚持性差。因此，促进新哮喘药物的发现和开发的研究是一项重要的研究。 许多NIH机构的优先事项，并反映在许多资助机会，包括SBIR/STTR。 Holoclara公司是一家早期的制药公司，基于对蛔虫的突破性发现， 衍生的免疫调节的合成小分子。人类临床试验和动物模型研究 发现蛔虫感染减轻了炎症和自身免疫性疾病的症状， 哮喘我们已经发现了一种新的小分子，HC-C（ANOM#7），来源于蛔虫提取物。HC-C 可以合成，我们最近的出版物表明，腹腔注射HC-C可以防止 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 明确的抗炎作用，通过影响先天性和适应性抑制2型免疫反应 这些模型中的免疫力在该1期申请中，我们建议确定HC-100口服给药的疗效。 C在慢性屋尘螨（HDM）小鼠变应性肺部炎症模型中的作用（目的1），并进一步探讨 通过测试HC-C对人气道平滑肌（HASM）的信号传导和功能的影响， 细胞和人气道上皮（HAE）细胞（Aim 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炎症的影响 重塑目的2将评估HC-C对促收缩信号传导和细胞凋亡的剂量依赖性作用。 哮喘和非哮喘供体培养物中HASM的收缩。HAE培养物，也来自 将用于测试HC-C对IL-13的剂量依赖性作用。 诱导的细胞因子、粘液产生和转录组调节。总的来说，这些研究将实现 重要的临床前目标，先进的概念验证和对机制的洞察，并证明 生产用于临床新药申请（IND）的HC-C-使非临床研究能够提交 FDA的IND。

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.