UI cystic fibrosis researchers receive $11.5 million NIH grant to develop new therapies

A team of cystic fibrosis experts with University of Iowa Health Care has been awarded a five-year, $11.5 million grant by the National Heart, Lung, and Blood Institute to research molecular therapies for cystic fibrosis (CF) lung disease.

“The overall goal of this program project grant is to better understand the cellular basis of CF airway disease and use this knowledge to direct new therapies towards its prevention or treatment,” says Paul McCray, MD, principal investigator of the grant and a professor in the UI Stead Family Department of Pediatrics, and the Department of Microbiology and Immunology in the UI Carver College of Medicine.

Cystic fibrosis is a common, life-shortening, inherited disease that causes progressive lung failure due to recurrent infections and airway obstruction. In the 30 years since the genetic cause of CF was discovered, major advances in understanding the disease have led to new therapies for people with most forms of CF. Work by the UI team has been instrumental in many of these discoveries.

CF is caused by multiple gene mutations, all of which damage an important ion channel protein called cystic fibrosis transmembrane conductance regulator (CFTR). With the new grant, the UI scientists led by McCray, Michael Welsh, MD, and John Engelhardt, PhD, will focus on developing new molecular therapies, including gene repair and small molecule drugs, that can treat CF and improve outcomes for patients regardless of the exact genetic mutation causing the disease.

Using several unique animal models and cell technologies they have created, the UI researchers will pursue three projects that aim to fix or replace the damaged ion channel, and also understand the basic biology of recently discovered airway cells.

• McCray will lead a project to develop and test very precisely targeted versions of CRISPR gene editing to restore the function of the CFTR channel in airway cells.
• Welsh’s team will focus on a small drug molecule that they recently found could mimic the properties of the ion channel. They aim to investigate how this molecule, known as amphotericin, works and potentially lay the groundwork for clinical trials.
• Engelhardt and his team will focus on a type of lung cell called an ionocyte to better understand the role it plays in defending the lungs from inhaled particle and pathogens, especially in CF.

“We are very grateful for major grant funding like this, which allows us to tackle big questions about how to treat cystic fibrosis and lung diseases in general,” McCray says. “There has been tremendous progress in CF treatments in the last decade, but there is still work to be done. With the new technologies and knowledge we’ve created, we are in an exciting position to make those advances for CF care.”

The UI researchers are collaborating with colleagues at other universities and private companies on these studies, including:

• Martin Burke, MD, PhD, at the University of Illinois, Champagne-Urbana, Ill.
• Randy Prather, PhD, at University of Missouri, Columbia, Mo.
• David Guay, PhD, at Feldan Therapeutics, Quebec City, Canada
• David Liu, PhD, at the Broad Institute, Harvard University, Cambridge, Mass.