Using plants to study new ways of delivering drugs for pulmonary hypertension
By Morgan Sherburne
Researchers at UF Health and the University of Pennsylvania have identified hormones that can be used to treat pulmonary hypertension, a disease with few treatment options. The twist? The hormones are grown in the leaves of plants at a high-tech greenhouse at the University of Pennsylvania.
In patients with pulmonary hypertension, the arteries of the lungs become constricted, which forces the heart to work harder to pump blood through the lungs. Over time, the heart’s right chamber, usually small, becomes enlarged and dysfunctional.
Currently, the most successful drugs for the disease cost tens of thousands of dollars, said UF researcher Vinayak Shenoy, Ph.D., one of two lead authors of the paper.
“Pulmonary hypertension is relatively a rare disease. It’s been neglected by the industry, and so there aren’t many drugs out there,” said Shenoy, an assistant research scientist in the UF College of Pharmacy’s department of pharmacodynamics. “The first drug for pulmonary hypertension was approved in 1995, although the disease was known since the early 1900s.”
Mohan Raizada, Ph.D., a distinguished professor of physiology and functional genomics in the Evelyn F. and William L. McKnight Brain Institute of UF, said blood pressure is regulated by key hormones. Too much of one hormone, angiotensin II, raises blood pressure. However, angiotensin II typically is balanced by two other hormones that maintain normal pressure, according to previous research by Raizada, Shenoy and Michael Katovich, Ph.D., a professor in the UF College of Pharmacy.
Their studies have shown that increasing the amount of these hormones in the body prevents pulmonary hypertension. But the researchers needed an effective way to deliver the hormones to test their therapeutic potential. Because the hormones are already found in the human body, Raizada said they had little concern about potential side effects.
“All of the drugs on the market so far for hypertension and cardiovascular diseases are based on inhibiting angiotensin II and aren’t very effective,” Raizada said. “Many years ago, we began to question why the prevalence of hypertension and cardiopulmonary diseases does not decrease when you inhibit angiotensin II. Instead, we thought we should be targeting the hormones that balance angiotensin II.”
Shenoy, Katovich and Raizada collaborated with Henry Daniell, Ph.D., a co-senior author on the study and director of translational research at the University of Pennsylvania’s School of Dental Medicine. Daniell studies drug delivery using plants, and introduced the human hormones into plant chloroplasts of tobacco, which then were grown, freeze-dried, enclosed in capsules and fed to groups of eight to 10 rats. To make sure the proteins could survive the acids and enzymes in the stomach, but could also travel across the intestinal wall and into the bloodstream, they were fused with a protein that binds to intestinal cells.
“The proteins we were dealing with are very large and unstable, only lasting a few minutes in the bloodstream when given as an injection,” Daniell said. “We needed to find a way to stabilize the proteins to increase their lifespan in the bloodstream and make sure it was working the way we wanted it to.”
When patients are treated with other medications, they typically see only a slight improvement — about a 10 percent reduction in pulmonary pressure. After the rats with established pulmonary hypertension had been treated with the medication for two weeks, their pulmonary pressure was reduced by 20 percent. After four weeks of using the plant-delivered medication to treat rats with pulmonary hypertension, the researchers found that the medication reduced pulmonary pressure by 32 percent.
Although pulmonary hypertension causes vessels in the lungs to constrict, patients actually die from heart failure. But the drug also improved function on the right side of the heart, potentially lowering the risk of heart failure, Shenoy said.
Next, the researchers hope to test the drug in people.
“The bottom line is we have been able to find a revolutionary way to deliver a therapy through oral delivery for a disease which is in critical need for an immediate innovative therapy,”
The study was funded by the National Heart, Lung and Blood Institute, the National Institutes of Health and the American Heart Association.