Modified Gene Therapy Better for Heart

Researchers learn to target tissue for treatment in mice

MONDAY, Jan. 19, 2004 (HealthDayNews) -- Scottish researchers report a promising step toward solving a major challenge in the budding field of gene therapy for heart disease by discovering how to get the gene to the cells that need the help.

"One problem with using this technology is that the virus that carries the gene go predominantly to the liver," says Andrew H. Baker, a reader in molecular medicine at the University of Glasgow. "We want to get the virus to home in on target cells in the heart."

Baker and his colleagues are working with adeno-associated virus (AAV), which is harmless to humans and is commonly used as a carrier in gene therapy work. When injected into the body, most AAV ends up in the liver, whose job is to clean the body of such foreign material.

The Scottish researchers report in the Jan. 20 online issue of Circulation that they have redesigned the surface of the virus so that it includes two peptides that bind with the cells that form the inner lining of blood vessels. These vascular endothelial cells are logical targets for gene therapy aimed at preventing arteries from clogging.

"What we are publishing is proof of principle, studies which show that if you select the proper peptides, you can incorporate those into the virus coat protein. In our mouse model, these viruses accumulate at target cells in the heart," Baker says.

While the work now is being done with heart cells, the technique is potentially applicable to other kinds of gene therapy, he says.

"If you incorporate peptides that target specific cells, you can use it for the kidneys, liver or what have you," Baker says. "If you are targeting cancer, you can treat cancer that is disseminated throughout the body."

In the animal trials, almost all unmodified AAV ended in the liver, while liver uptake of the modified virus "was significantly lower than with native AAV," the report says.

And the modified virus remained active in the heart for a long time. Tests showed the experimental gene carried by the virus was still active four weeks after it was injected, so that even a single injection of the modified virus might provide effective treatment, Baker says.

"This is very exciting work," says Dr. Jeffrey S. Borer, who heads the Division of Cardiovascular Pathophysiology at Weill College of Cornell University. "It is potentially an important paper."

A lot of work remains to be done, Borer says. "Now one needs to design a therapeutic gene, put it into an appropriately targeted AAV and use it for treatment," he says. "In theory, it should make a difference. But the important thing is that they have proved the principle that you can affect the viral coat."

The technique also raises the possibility of reducing the adverse side effects of gene therapy, Borer says. Researchers now must inject large amounts of gene-carrying viruses to make sure that enough reaches the target cell, and those injections can cause fever and other problems. Much smaller amounts of targeted viruses may achieve the goal, he says.

More information

The whys and wherefores of gene therapy can be found at the American Heart Association or the Human Genome Project.

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