UF researchers score gene therapy advance: Animal study shows high blood pressure prevented in future generations

November 10, 1999

GAINESVILLE---A form of gene therapy to ward off high blood pressure in rats appears to permanently alter the animals' DNA blueprint, preventing their offspring from inheriting the disorder, University of Florida scientists report today (11/12) in Circulation Research: Journal of the American Heart Association.

The advance represents the first time researchers have been able to protect future generations through gene therapy for any condition, said UF molecular physiologist Mohan K. Raizada. Other studies have shown random bits of inserted genes can be passed on, but with no therapeutic effect. The new approach involves using a form of genetic brilliance to block the action of a harmful hormone, angiotensin, which causes blood vessels to narrow, increasing blood pressure.

"The neat part of this study is we're able to show both the effects on high blood pressure as well as on the organs involved in the control of blood pressure," Raizada said. "We have shown that this form of gene therapy not only prevents these animals from developing high blood pressure but also prevents a lot of other types of pathophysiological changes in the heart, the kidney and the arteries."

What's more, after studying two subsequent generations of rats - the original animals' "children" and "grandchildren" - researchers discovered the beneficial changes were passed on. Those offspring should have had high blood pressure but didn't, said UF vascular biologist

Craig H. Gelband. Raizada and Gelband, who are affiliated with UF's College of Medicine and the campuswide Genetics Institute, collaborated with Michael J. Katovich, in the university's College of Pharmacy on the study. The project was funded by the National Institutes of Health and the

American Heart Association's Florida affiliate. Findings from related research also were presented at this week's annual meeting of the American Heart Association in Atlanta.

While it may be years before the approach is tested in people, the research could represent a first step toward improving the treatment of, or even preventing, high blood pressure and related health problems in humans, Raizada said.

"Our observations are very exciting in the sense that for the first time there is a possibility of permanent control of high blood pressure involving gene therapy," he said. "Where that leads to as far as human therapy is concerned is far away. We have many hurdles to jump. For example, our studies have shown we can prevent the development of high blood pressure. But in humans, there are no gene markers to define that a person is going to develop high blood pressure. The key would be to find therapies that would reverse high blood pressure once it has been established."

To date, gene therapy in humans has been limited to trying to correct existing disease in a way that does not permanently alter a person's DNA makeup. Raizada noted that before U.S. policy would ever change to allow such studies in people, a wide range of scientists, ethicists

and public policy specialists would debate the issue, taking into account the implications of changing patterns of heredity.

An estimated 50 million Americans battle high blood pressure, according to the national Centers for Disease Control and Prevention. The condition affects almost all the body's vital organs, particularly the heart and kidneys, changing their structure and altering their ability to function properly. It is a major risk factor for stroke, hardening of the arteries, heart failure, heart disease and kidney damage.

While medication controls high blood pressure in many patients, it can cause adverse effects such as persistent cough or even low blood pressure.

The hormone responsible for regulating blood pressure, angiotensin, acts at specialized sites known as receptors, located on the surface of cells. During their study, UF researchers rewrote the genetic message that typically orchestrates the creation of these sites. They then packaged the genetic material into a virus modified so it wouldn't cause illness and injected it into the rats. The virus, acting much like a car delivering passengers to a destination, transported the genetic material into the rats' cells, instructing them to halt production of the hormone's receptor sites.

Gelband noted that unlike most other viruses tested in gene therapy, the one UF researchers used appears to act differently once it enters a cell's nucleus, the cell's "command post."

"We've shown that our vehicle for the gene therapy, a retrovirus, actually integrates into the animals' DNA, and this may be the reason why it gets passed on to the next generations," Gelband said.

While UF researchers heralded the therapy's advantages, they also struck a cautionary note: All gene therapies have to be carefully scrutinized to see what effects gene transfer has on the genetic characteristics of subsequent generations.

"We as scientists have got to be very careful," Raizada said. "What are the physiological consequences? We must not predispose ourselves to thinking there are no side effects to permanent changes, and we should always guard for that."

University of Florida

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