2 New Cystic Fibrosis Studies to be Stepping Stones to Future Research

A Case Western Reserve University researcher is starting two studies, based on angiotensin signaling and gene “correction,” to advance research into more effective ways of treating cystic fibrosis (CF) and to better understand the ideal timing for such interventions. Both studies will begin in January.

CF is due to a defective gene that causes a thick buildup of mucus in the lungs, pancreas, and other organs. In the lungs, mucus-clogged airways result in cyclical infections and damage. It is estimated 70,000 people worldwide have CF, and 1,000 new cases are diagnosed every year, mostly in newborns. Available treatments target CF symptoms but no cure has been found.

Rebecca Darrah, PhD, assistant professor at the Frances Payne Bolton School of Nursing and assistant director of Case Western Reserve’s Genetic Counseling Training Program, will lead the studies into gene manipulation and modification. “With these new studies, we are hoping to not only develop new treatment strategies that would benefit all CF patients, but also determine the ideal timing for other clinical interventions already in place to help patients with specific mutations,” Dr. Darrah said in a press release.

The first study will examine the potential benefits of medications, such as ACE inhibitors, designed to lower blood pressure and regulate fluid balance. Scientists know that worsening lung symptoms in CF patients are connected to variations in the genetic code of an angiotensin pathway receptor that restricts vessels and raises blood pressure. Dr. Darrah and her team will study the effects of altering this pathway in genetically modified mouse models to determine whether such alterations ease CF symptoms. They also want to see if giving the CF-treated mice medication designed to alter angiotensin signaling will improve their breathing. Since U.S. Food and Drug Administration (FDA)-approved hypertensive drugs targeting the angiotensin pathway exist, Dr. Darrah believes this study could readily lead to clinical trials in CF patients. Funding for this study is being provided by Gilead Sciences, Inc.

A recent genetic survey of CF patients also suggested they might benefit from drugs like ACE inhibitors that treat high blood pressure.

The second study, funded by the Cystic Fibrosis Foundation, aims to help design more effective clinical trials by uncovering important new data. Researchers will use CF mouse models treated with a drug to try and modify — “correct” — the genetic mutations that cause the disease. There are three specific issues they hope to determine: 1) which respiratory symptoms are reversible or preventable with genetic correction; 2) the ideal timing for the genetic correction (i.e., in infants or adults); and 3) the amount of genetic correction required (i.e., would partial correction suffice to alleviate or prevent symptoms, or must the gene be completely corrected?).

“Treating chronic diseases, such as CF, can be clinically challenging because it is often unclear whether disease symptoms can be reversed or whether the best hope is just to slow the progression of the disease,” Dr. Darrah said. “With clinical trials of new drugs to correct the genetic defect that causes CF, knowing the ideal timing of this treatment is critical.”