United Press International - Friday, February 12, 1999

Investigators at Duke University Medical Center now report they have engineered a "stealth virus" that evades the immune system's "radar."

The scientists have modified a common cold virus to remain quiet, or invisible to the immune system. This virus can not only carry its cargo of corrective genes to target cells, but can persist at the site for months at a time without being rejected by the immune system.

The scientists believe their results, reported in the current issue of the journal Human Gene Therapy, overcome a barrier to the use of the adenovirus as a genetic delivery vehicle.

"If our approach is confirmed by further studies," says Andrea Amalfitano, a Duke pediatric geneticist who lead the team, "these modified adenoviruses may have great application for gene therapy in the future."

Severe genetic disorders such as cystic fibrosis, muscular dystrophy, retinitis pigmentosa are among the candidates for gene therapy. Adenovirus has long been considered an excellent "vector" for gene delivery. The virus can infect almost any cell and be grown in vast quantities. But within three weeks of the virus's introduction into the body, the immune system recognizes it as foreign and wipes it out, along with its genetic payload, and cells infected with the new genes.

To understand why the adenovirus gets caught, Amalfitano and his group developed a "two-hit" hypothesis. In this theory, hit one comes when the immune system recognizes the virus as foreign. Hit two arrives when the immune system recognizes the introduced gene as foreign. But it is only after both hits are stimulated simultaneously, says Amalfitano, that "a threshold is reached and the immune system says 'Hey, there's something strange here, let's get rid of it.' And eliminates the virus from the body."

It is the combination of the first and second hit, he thinks, that must occur for the immune system to attack. "Hit one or hit two by themselves don't elicit the danger signal."

Following previous research techniques, Amalfitano's group deleted a gene called "E1" from the adenovirus. Uniquely, the group engineered a second modification into the virus. This rendered the modified virus quiet to the immune system, prevented the hit-one stimulus from ever occurring, and conferred the stealthiness to the virus as it delivered the beneficial genes to the targets.

The researchers injected mice with the stealth virus. Within three days it had infected every liver cell where it remained for over two months. In a control group of mice treated with a "non-stealth" adenovirus, the virus was eliminated within three weeks.

"I'm not saying the immune response is completely eliminated," Amalfitano says, "But a certain arm of the immune system is not being triggered and the virus is allowed to persist for an extended period of time.

"I feel this virus has the potential to overcome at least one aspect of the immune response problem of viruses in gene therapy," he continues.

"We haven't solved the whole problem, but it gives us a clue that with further work it will only get better."

More animal tests involving different tissues and different genes are necessary before this therapy can go to human trials for the treatment in genetic diseases, he said. "We're trying to retain the good things in adenovirus, while getting rid of the less desirable aspects, one of which is the immune response."

"Amalfitano is trying to address a tough and important problem in gene therapy," said Dr. James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania. "Whether it's an advance beyond some of the other attempts is not yet clear. But he is heading in a new direction, and more importantly, providing a conceptual framework on which to understand this problem."

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