New method targets sites for gene therapy.

New method targets sites for gene therapy

With federal agencies on the brink of approving the first U.S. injections of therapeutic genes into humans, researchers have begun devising strategies to direct these genes to the specific body tissues that need them. A new report suggests that tiny balloons threaded into blood vessels may help gene therapists perform site-specific gene insertions.

The first human gene-therapy experiments likely to gain government approval involve injections of genetically engineered cells that can do their job while circulating freely throughout the body, or can find their own way to their intended destinations (SN: 6/16/90, p.380). But in the future, says Gary Nabel of the University of Michigan Medical Center in Ann Arbor, physicians will want to constrain certain gene-altered cells within smaller areas so they secrete their therapeutic compounds only where needed.

In previous research, Nabel and others implanted genetically engineered cells into targeted blood vessels in pigs and dogs (SN: 6/17/89, p.373). But that procedure was rife with hassles, he says. The cells had to come from a compatible donor, and it took about five weeks to engineer them in the laboratory. Now, Nabel's team has a better method.

With co-workers Elizabeth G. Nabel and Gregory Plautz, Nabel has adapted a common medical procedure used by cardiologists to open clogged blood vessels. The technique, called balloon angioplasty, normally involves threading a catheter containing a tiny, uninflated balloon into a constricted vessel, then briefly inflating the balloon to compress accumulating deposits against the vessel walls.

The researchers used a customized catheter with two balloons. Working with pigs, they inflated both balloons, leaving the stretch of vessel between the balloons temporarily isolated. Into that space they injected several thousand copies of the desired gene -- in this case, one that is nontherapeutic but easily trace. Within minutes, the genes -- which the researchers had packaged in either viral "shuttles" or fatty globules called liposomes -- made their way into cells lining that length of blood vessesl. The genes remained active in those cells for up to 21 weeks and settled nowhere else in the body, the team reports in the Sept. 14 SCIENCE.

"The idea is a very clever one. It's an exciting advance," says W. French Anderson of the National Heart, Lung and Blood Institute, who is awaiting final permission to perform the nation's first human gene-therapy experiments. "The question is going to be: Can you get sufficient gene activity in that site?" He says it remains uncleasr whether the relatively small number of gene-altered cells in a few centimeters of vessel can deliver enough of a therapeutic effect.

Nabel thinks the technique may prove useful for delivering small, constant supplies of a drug to specific locations. For example, he says, stretches of blood vessels prone to cloging by recurrent blood clots could be engineered to secrete clot-busting drugs. Or vessels supplying blood to tumors could be engineered to secrete cancer-fighting compounds such as tumor necrosis factor, he says.