Feb. 2, 1999 TORONTO -- Researchers at The Hospital for Sick Children (HSC) have successfully used biological engineering to prevent the closing of a key passage between the two large blood vessels leading out of the heart to the body and lungs. The passage, called the ductus arteriosis, normally closes shortly after birth, but the survival of newborns with severe heart defects depends on the ductus remaining open, at least until corrective surgery can be carried out.
Dr. Marlene Rabinovitch, HSC's head of Cardiovascular Research, holder of the Heart and Stroke Foundation of Ontario Chair, and a professor of Paediatrics at the University of Toronto, used a gene transfer process in her animal research to deliver a "decoy gene" that tricks cells into thinking they don't have to make a substance critical to the ductus closing process.
In normal heart development, the ductus closes within hours of birth and the lungs take over the task of oxygenating the blood. The ductus is sealed by cushions that grow together from each side of the passage. This seal prevents the back flow of blood into the heart, which can cause congestion and heart failure. But infants who are born with severe heart defects, such as blocked valves, rely on an open ductus to ensure that blood gets to the body.
"Keeping the ductus open ensures that the blood keeps flowing throughout the body, buying the baby time until surgery can be carried out to repair the heart defect," explains Dr. Rabinovitch.
The cushions that seal the ductus are made of muscle cells that migrate to the ductus along a slippery substance called fibronectin. In her research, Dr. Rabinovitch used a "decoy" gene to trick the cells into thinking they don't have to make fibronectin. Without it, muscle cells can't travel to the site of the ductus.
"Basically, we pulled the rug out from under the muscle cells as they were on their way to block off the ductus," explains Dr. Rabinovitch.
Almost one in 100 infants are born with a heart defect requiring open-heart surgery. Defects are often identified before birth through the use of fetal ultrasound. Usually the infants are treated with a hormone called prostaglandin, which helps keep the ductus open. However, prostaglandins need to be given continuously by intravenous and are associated with serious side effects such as low blood pressure and irregular heartbeats. The development of a bioengineering approach to keep the ductus open could lead to a more effective and safe way to help infants with serious heart problems survive.
"The next step in the research will be to develop a method for delivering our "decoy gene" directly into the necessary cells before the baby is born," explains Dr. Rabinovitch. "We also anticipate that successful biological engineering of the ductus can be applied to other heart problems, such as preventing the reclosing of arteries after angioplasty."
This research was funded by the Medical Research Council of Canada and The Hospital for Sick Children Foundation.
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