Development of a Nematode-Derived Drug to Treat Asthma

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.