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.

Grant Number: 1R21AI182936-01A1
NIH Institute/Center: NIH
Principal Investigator: Yan Bai