Sildenafil, antioxidants, and gene therapy for cystic fibrosis treatment are part of an arsenal of studies in progress at Medical College of Georgia at Georgia Regents University. At the heart of the action is Dr. Ryan A. Harris, clinical exercise physiologist at the Georgia Prevention Institute at the college. Dr. Harris’ laboratory has shown that cardiac function may negatively affect exercise capacity of cystic fibrosis patients even if patients have adequate lung function.
“We want to understand why these patients have blood vessel dysfunction and exercise intolerance even though there are all these new therapies improving their lung function,” said Dr. Harris in a news release from the college. “Right now we are looking at mechanisms that may be contributing to these problems but we also need to develop treatments that will provide sustained improvement.”
Although sildenafil, a muscle relaxer that increases blood flow and is used for pulmonary hypertension (Revatio) and erectile dysfunction (Viagra), and antioxidants are not being pursued as sustainable treatment options at present, they are tools to understand the reasons for poor exercise capacity. Dr. Harris previously identified leg fatigue as one of the culprits, rather than lung capacity, due to insufficient blood and oxygen supply. His finding was first reported in 2012 in CHEST Journal in collaboration with Dr. Katie T. McKie, Director of the Pediatric Cystic Fibrosis Center at Georgia Regents University Children’s Hospital of Georgia.
The research group is administering low doses of sildenafil to adult patients multiple times daily for four weeks. Before and after treatment, patients are tested for endothelial function and exercise capacity. It is thought sildenafil will increase blood flow and retrain the blood vessels to respond more normally to exercise. “There is evidence in others who use it that blood vessels improve,” said Dr. Harris.
Another strategy for studying exercise capacity in cystic fibrosis patients is administering a combination of over-the-counter antioxidants. Patients with high levels of oxidative stress and chronic inflammation are the target audience for therapy. Dr. Harris expects to see similar results to sildenafil treatment: an immediate, albeit temporary improvement in exercise capacity.
Ultimately, Drs. Harris and McKie believe the root cause of endothelial dysfunction is a reduced ability of blood vessels to respond appropriately in different scenarios: for example, dilating when the body needs more blood and oxygen during exercise. The altered response may be a result of chronic inflammation and oxidative stress that impairs the use of nitric oxide to dilate blood vessels.
Also of interest to the group is gene therapy to directly address dysfunctional chloride channels that contribute to the sticky, glue-like mucus that accumulates in the lungs. The team is collecting baseline measures of endothelial function and exercise capacity for patients who qualify for combination gene therapy that is projected to be available next year.
Before these projects were fully initiated, Drs. Harris and McKie noticed a difference between the way healthy individuals and cystic fibrosis patients use oxygen. Oxygen saturation at rest was lower for patients, and oxygen consumption was 14% lower during peak exercise. Expelled oxygen was richer in oxygen, which indicated poor muscle efficiency for oxygen usage. Adding to this is the fact that blood vessel dilation is poorer for patients. Significantly less dilation is observed for patients than healthy individuals who are wearing a cuff that increases blood flow through the arm.
The three projects are funded through grants from the National Institutes of Health, the Cystic Fibrosis Foundation, and Vertex Pharmaceuticals Inc. Unique to the studies is the focus of treatments. “All the existing therapies are primarily tied to lung function,” said Dr. Harris. “We are bringing a new dimension to the table. [Patients] are going to feel better, have less pulmonary exacerbations, less infections, less systemic disease.” Any improvements would only build upon the success of current treatments in raising the life expectancy of cystic fibrosis patients from five years in 1950 to forty years currently.