# Project 3: Soluble Guanylate Cyclase Activators as Bronchodilator in Asthma

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $520,431

## Abstract

ABSTRACT – PROJECT 3
Airway inflammation, remodeling, and hyper-reactivity are defining features of asthma, and typically associated
with higher than normal levels of nitric oxide (NO). Bronchodilators, such as beta-agonists targeting the β-
adrenergic receptor (βAR)-cyclic AMP pathway, are the backbone of current therapy. However, asthmatic
patients have heritable variability of beta-agonist response and some become unresponsive to beta-agonists
with time, all of which limit therapeutic efficacy. Soluble Guanylate Cyclase (sGC) is the NO receptor and
triggers smooth muscle relaxation, but paradoxically, the high NO in asthma is associated with greater airway
hyper-reactivity. TPPG Cycle I studies identified that high levels of NO and oxidants in asthmatic airways
damage sGC, making it NO-insensitive and diminishing the NO-sGC pathway from acting in bronchodilation. In
preliminary data with Core C, CII-Project 3 now shows that pre-constricted human and murine airways
bronchodilate in response to a new class of drugs that target the two states of sGC: its NO-sensitive form
(stimulators), and its NO-insensitive damaged form (activators). In the ovalbumin and house dust mite murine
models of asthma, single acute administration of an sGC-activating drug induces bronchodilation and prevents
airway hyper-reactivity in response to methacholine. Together with Core B and Pharma partners, Project 3
aims to reposition the sGC-activating class of therapeutics - recently launched by Bayer and Ironwood for
pulmonary hypertension and inflammatory bowel diseases, respectively - for the treatment of asthma. Project 3
tests the hypothesis that sGC drugs can be repurposed for asthma by: (Aim 1) comparing the efficacy of sGC
activators/stimulators with beta-agonist drugs in preclinical models of asthma endotypes (TH2 and TH17); (Aim
2) analyzing mechanistic endotypes of sGC inactivation and/or AR dysfunction that underlie the abnormalities
in bronchomotor tone, airway inflammation, and remodeling in preclinical models; and (Aim 3) testing blood
cells of asthmatic patients in comparison to controls for sGC and βAR activities to develop a bronchodilator(s)
drug response profile test. An ability to define asthmatic populations who would likely benefit from specific
classes of bronchodilators (sGC and beta-agonist), using our new functional biomarker assessment of
bronchodilator response, will be a large step forward in personalized medicine approaches for asthma, and
reveal the market share available for the sGC class of bronchodilators. Project 3 works synergistically with
Project 2 and Core B in preclinical asthma, and with Projects 1, 2 and Core A for clinical studies. Core B and
Project 3 have designed strong pre-clinical translational studies that are essential to obtain FDA approval to
test sGC compounds for an asthma indication, and developed solid Pharma partnerships that have already led
to provision of sGC activators/stimulators and key laboratory support fo...

## Key facts

- **NIH application ID:** 9986008
- **Project number:** 5P01HL103453-10
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** DENNIS J STUEHR
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $520,431
- **Award type:** 5
- **Project period:** — → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986008

## Citation

> US National Institutes of Health, RePORTER application 9986008, Project 3: Soluble Guanylate Cyclase Activators as Bronchodilator in Asthma (5P01HL103453-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9986008. Licensed CC0.

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