By Lisa Seachrist

Washington Editor

In the wake of a fatality in a gene therapy program at the University of Pennsylvania, the FDA has ordered Schering-Plough Corp., of Madison, N.J., to halt two gene therapy studies that shared one key similarity: they used relatively high doses of adenovirus to introduce a new gene directly into the liver.

Despite the death of an 18 -year-old participant in the Penn study, the agency is allowing dozens of other gene therapy experiments to continue, including those using adenovirus as a vector. Industry analysts see the entire incident as evidence of the scrutiny under which the fledgling field operates.

¿We are only beginning to understand how all of this works,¿ said Tom Brakel, an analyst with Mehta Partners LLC in New York. ¿The scientific and regulatory community will be even more cautious about safety issues after this.¿

In September, Jesse Gelsinger, of Tucson, Ariz., died just four days after researchers at Penn in Philadelphia injected genes to cure a genetic metabolic disease called ornithine transcarbamylase deficiency. The researchers were using an adenovirus construct to deliver the genes. The protocol used a high dosage of the construct introduced directly into the hepatic artery.

FDA and Penn researchers are still trying to figure out what caused Gelsinger¿s death. Because adenovirus is known to cause inflammation, some scientists have speculated that a compromised liver can¿t handle a direct injection of high doses of adenovirus. Eighteen patients have been treated in the Penn study with none of the other 17 patients suffering any significant side effects.

The Schering trials are Phase II studies using adenovirus to deliver a different gene ¿ the anti-tumor p53 gene. The company is attempting to treat liver cancer and liver metastasis from colorectal cancer by introducing the p53 gene into the liver. Like the Penn study, the researchers in the Schering study are injecting the adenovirus construct into the hepatic artery.

The FDA has placed a hold on these clinical studies to review data. Schering isn¿t allowed to enroll new patients into the studies, but is permitted to continue treating patients with the p53-adenovirus construct. Patients receive five-day infusions into the hepatic artery every month.

¿To date, we¿ve not had any deaths associated with adenovirus vector,¿ said Robert Consalvo, spokesman for Schering. ¿We have supplied the FDA with all of our safety data to date on about 60 patients.¿

The agency will use the Penn and Schering data to see if it can identify a pattern that explains what happened to Gelsinger. While the agency and Penn researchers try to figure that out, gene therapy will continue to make progress toward eventual therapies.

¿I don¿t view the death of one patient as a setback for the industry,¿ said Lesley Marino, an analyst with BancBoston Robertson Stephens Inc. in New York. ¿So far, gene therapy has had a very good safety record. The rules for conducting gene therapy are fairly stringent and they will most likely continue under such scrutiny.¿

Brakel said Gelsinger¿s death will likely focus companies on gene therapy approaches that don¿t use adenovirus to deliver various genes.

¿Any company doing gene therapy has probably evaluated adenovirus,¿ Brakel said. ¿If you were looking at that now, you might strongly consider using a non-viral vector to deliver genes.¿

Marino said companies will continue to develop both adenoviral vectors and non-viral vectors, but the vector alone won¿t determine the success of a company.

¿I think gene therapy will emerge as a viable therapy,¿ Marino said. ¿At the end of the day, it doesn¿t matter whether you use an IV or an adenovirus. What will make the difference is if the therapy treats the disease.¿