Personalized, Small-Molecule Therapies for Severe Asthma and Cystic Fibrosis

Innovations in Pediatrics - Winter 2017 

Benjamin Gaston, MD

Jonathan Stamler, MD

 Mitch Drumm, PhD

Benjamin Gaston, MD, Division Chief, Pediatric Pulmonology, Allergy & Immunology, UH Rainbow Babies & Children’s Hospital; Professor of Pediatrics, Case Western Reserve University School of Medicine, recently received a $13.3 million grant from the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health to create new, personalized therapies for patients with severe asthma or cystic fibrosis (CF). He and his colleagues will test combinations of new drugs – developed principally by Dr. Gaston and his co-investigators – on airway cells from severe asthma or cystic fibrosis patients to understand which drugs will likely work best for individual patients.

“The idea is to get the right treatment to the right patient,” Dr. Gaston says. “It’s a new direction for NHLBI to personalize these therapies.”

Severe asthma and cystic fibrosis are being studied in the same program because there is overlap between the conditions. This provides an economy of scale for developing effective therapies. New agents for asthma patients could be effective for cystic fibrosis, and vice versa. “Companies are not always interested in seeing whether their drugs might work better in concert with other companies’ asthma and CF drugs,”Dr. Gaston says. So he and his colleagues will test certain combinations. 

In cystic fibrosis, a few new drugs on the market have greatly helped small numbers of patients, but they haven’t been as effective for the majority of patients. That’s because there is a lot of patient-to-patient variability in cystic fibrosis, even among patients with the same gene.

“There are nearly 2,000 known mutations in the cystic fibrosis gene, some that only one person on the planet may have,” says UH Rainbow genetics researcher Mitchell Drumm, PhD, Vice Chair for Pediatric Research, UH Rainbow Babies & Children’s Hospital and Case Western Reserve University School of Medicine, who discovered part of the cystic fibrosis gene as a graduate student at Case Western Reserve University School of Medicine in 1989. Indeed, Kalydeco, the first new drug to attack a cystic fibrosis gene mutation, was approved in 2012 for only one mutation, which relatively few patients have.

In contrast to cystic fibrosis, knowledge about the genes that control asthma is limited. One major part of the research will focus on a newly discovered gene called GSNO reductase (GSNOR), which controls airway size. People with higher levels of GSNOR are predisposed to asthma because it breaks down a naturally occurring molecule called S-nitrosoglutathione (GSNO), which keeps airways open.

“If the level of GSNOR goes up, then GSNO goes down, and its anti-inflammatory effects are lost,” says Jonathan Stamler, MD, President, Harrington Discovery Institute at University Hospitals and the Robert S. and Sylvia K. Reitman Distinguished Chair in Cardiovascular Innovation, UH Cleveland Medical Center and Professor of Medicine and Biochemistry, Case Western Reserve University School of Medicine, and a member of the research team. Dr. Stamler also will search both for drugs that can inhibit the production of GSNOR and for mutations of GSNOR that may greatly affect its activity. Controlling those might help restore adequate GSNO levels in patients’ airways.

In related work, Dr. Gaston will test whether merely raising the pH of children’s airways with alkaline solutions will allow treatment drugs to work better. Many children with severe asthma or cystic fibrosis have chronically acidic airways.

“It can be damaging,” Dr. Gaston explains. “It also makes drugs less effective.” Consider the commonly used bronchial dilator Albuterol, for example. “If you raise the airway pH, it works better.”

Contact Drs. Gaston, Stamler and Drumm at Peds.Innovations@UHhospitals.org.

All National Institutes of Health funding for basic and clinical research is awarded to the School of Medicine at Case Western Reserve University.