Gene Treatment Makes Change of Heart

by Cassie Ferguson

Gazette Staff

Using a new technique to slip bits of DNA into a beating heart, Harvard researchers have found a genetic way to adjust its tick.

Researchers at Harvard-affiliated Massachusetts General Hospital (MGH) tested the procedure in normal rats, giving their good hearts a bad gene that also causes a common form of heart disease in humans.

"Now, using that technique we can help the heart," said Roger Hajjar, an instructor in medicine at MGH. "We know the genes that can be beneficial and we can take the same technique and express those genes."

The technique may some day be useful as a method to deliver gene therapy as a treatment for heart disease. Heart disease, said Hajjar, accounts for most admissions to the hospital for people over 65.

Though the technique is far from being practical for use in humans, cautioned Anthony Rosenzweig, assistant professor of medicine at the Medical School and MGH, in the rats it was a "dramatic success."

Previous attempts at transferring genes to the heart have been limited to sections of the heart muscle, said Hajjar.

In a study published in the current issue of The Proceedings of the National Academy of Sciences, Hajjar, Rosenzweig, and their colleagues at MGH took the new approach of injecting a solution containing the genes into the aorta and clamping it shut beyond that point, forcing the solution through all the vessels that feed the heart. This procedure flushed the solution throughout the heart muscle, even changing the heart's color as it rushed through the veins.

The researchers decided to test the new technique using a gene that is associated with heart failure in both humans and rats. It works by increasing the levels of a protein called phospholamban that debilitates the heart's left ventricle. The left ventricle gives blood its final push away from the heart toward the rest of the body.

Hajjar spliced the DNA into a weakened, nonreproducing virus and, using the new technique, infected 50 rats.

"It's like a delivery truck and you put in what you want. Then you see what happens," said Hajjar.

Two days later, the genes began to take effect, the new DNA ordering the heart cells to make the new protein. The heart slowed down and the pressure in the left ventricle dropped to half of normal. This matches what happens in humans when congenital heart disease has damaged the heart muscle, making it grow abnormally weak, said Hajjar.

However, he noted, after a week the immune system recognizes that particular type of delivery truck and its contents and destroys them. But, he added, this can be remedied using newly developed delivery systems engineered to evade the immune response.

The new gene-delivery technique will give researchers a way to study the specific effects of genes on heart muscle.

"By probing with one gene at a time, you can target just one pathway in the heart and nothing else," said Hajjar. "It allows us to take it to the next step to try to see whether specific genes can be helpful in heart failure."

In fact, Hajjar said, unpublished data from his most recent experiments show that the administration of beneficial genes to rats during heart failure has already been a success.