Harnessing the soluble guanylate cyclase pathway to alleviate early life RSV bronchiolitis - Project Summary: Respiratory Syncytial Virus (RSV) infection is the most common cause of hospitalization in young children, leading to respiratory failure and even death in severe cases. Viral bronchiolitis with airflow obstruction is the cardinal pathophysiology of RSV infection in early life. Unfortunately, conventional bronchodilators fail to dilate RSV-constricted airways adequately. To fill this therapeutic gap, we focus on the contractile deregulation of airway smooth muscle (ASM) and propose to develop a novel bronchodilation strategy. In preliminary studies, we observed that RSV infection impairs both the β2-adrenergic receptor (AR)-mediated and the nitric oxide (NO)- mediated ASM relaxation pathways. Strikingly, these ASM relaxation deficiencies can be fully overcome by activating the cGMP pathway downstream of NO, using the soluble guanylate cyclase (sGC) agonist, Bay 60- 2770. Indeed, in non-RSV settings, adjacent published studies have revealed that Bay 60-2770 is equally effective as conventional β2-AR agonists in relaxing ASM and even advantageous because it does not lose effect as the β2-AR agonist by receptor desensitization. Empowered by these preliminary and published data, we propose the central hypothesis that soluble guanylate cyclase (sGC) agonists can serve as effective bronchodilators in RSV-infected pediatric airways. Among nearly 75 known sGC activators and agonists, we pick 8 compounds that are either FDA-approved or at late-stage (meet Phase 2 endpoints) clinical development and assess them for drug repurposing towards bronchodilation in RSV-infected pediatric airways. In Aim 1, we will utilize the RSV-infected pediatric PCLS to screen the 8 clinically relevant sCG agonists and Bay 60-2770 for bronchodilation efficacy and assess their potential cell toxicity. Using the non-toxic top 3 hits, we will further examine their relaxation effect in the presence of tracheal aspirate from pediatric patients intubated for severe RSV infection, study the mechanisms underlying the NO-independent sGC-mediated relaxation with primary ASM cells, and explore the drug impact on RSV-induced epithelial infection and inflammation. In Aim 2, we will use the mouse PCLSs from the BALB/c pup model of RSV infection to demonstrate the airway relaxation effect and drug safety of Bay 60-2770 and the top 3 hits from Aim 1. Then, we will administer the hit candidates to RSV-infected BALB/c pups and evaluate their therapeutic impact on airway resistance, viral clearance, and lung inflammation at the acute infection stage and 4 weeks after viral exposure. This project addresses a long-existing clinical challenge in managing obstructive respiratory failure in severe RSV bronchiolitis of young children. It lays the foundation for a novel therapy targeting the relaxation defect by repurposing the NO-independent sGC agonists already in clinical trials.
