Gene therapy safety in question again

By Tina Hesman Saeyand Amy Maxmen
ST. LOUIS POST-DISPATCH, Jul. 27 2007

A research group led by scientists from Washington University and St. Louis University released a study today showing that a genetically altered virus used in human gene therapy trials causes liver cancer in mice.

The findings follow the announcement Thursday that a patient in Seattle died earlier this week after being treated with the same virus. The cause of the patient's death is unknown, but the Food and Drug Administration is reviewing whether 29 human trials using the virus should be allowed to continue.

The treatment, using a virus called adeno-associated virus, is considered one of the most promising avenues for battling genetic diseases such as cystic fibrosis and muscular dystrophy.

"The bottom line is we need more research so that we can really define the risk," said Mark Sands, a Washington University researcher who led the cancer study.

In 2000, researchers at Washington University noticed that the mice they successfully treated for a liver disease using the adeno-associated virus were developing tumors. The virus had already been approved for use in clinical studies on humans.

Sands relayed the findings to the Food and Drug Administration, which oversees gene therapy trials, said Karen Riley, an agency spokeswoman. The FDA convened a safety panel to discuss those results and other safety concerns in March 2001.

"We decided that the safety profile was acceptable and should continue to be evaluated in clinical trials," Riley said.

Sands then pursued a new study, this time to verify whether the virus was directly responsible for causing cancer. About half of the mice treated with the virus got cancer. The results appear today in the journal Science.

"No one is more disappointed about these data than I am," Sands said. "With gene therapy we can cure this disease in mice. But I can't ignore the data. We were anxious to repeat our findings, hoping that the tumors were an artifact, but it's not," Sands said.

In gene therapy, healthy genes are inserted into a person with a genetic disease. One way to insert the gene is through a genetically engineered virus, which is injected into the patient. The healthy gene then makes proteins that reverse the disease.

The death in Seattle raises new questions about whether the virus should be used in human trials. The patient died after receiving a second injection of the gene therapy virus while being treated for arthritis during a clinical trial by Targeted Genetics Corp. The company has treated about 100 people in the trial without adverse affects, the FDA said Thursday.

While it remains unclear whether the virus played a role in the patient's death, the cancer finding is reason enough to step back from human studies, said Ronald Munson, a medical ethicist at the University of Missouri-St. Louis.

"Safety should be established in animals before it is tried in humans," Munson said. "I think therapy using this version of the virus should not go forward until we understand what has happened."

Still, several scientists, including Sands, say they aren't ready to abandon the virus in human studies, given its potential.

"The problem is that no one else has seen the same thing" as Sands, said Nick Muzyczyka, professor at the University of Florida and scientific adviser at Applied Genetic Technologies Corp. in Alachua, Fla. The company is conducting two gene-therapy trials using adeno-associated viruses and has several gene therapy treatments in development.

Meanwhile, Dr. Valder Arruda of the University of Pennsylvania deliberately attempted to use the virus to cause cancer in mice that were already predisposed to the disease. But the mice remained healthy.

While Arruda said he believes Sands' data, the technique is so complex that the virus alone may not be the problem, noting other complicating factors, such as the age of the animal.

Arruda and his colleagues began treating people for hemophilia with the virus in 2001. They have also been treating 30 dogs for hemophilia with the virus, some for more than five years. Thus far, neither the six humans nor the dogs have gotten cancer.

Medical research comes with a certain amount of risk, scientists say. For some reason, gene therapy is given less room for error, said Dr. Markus Grompe, director of the Oregon Stem Cell Center in Portland.

"In general we have a tendency to not accept any side effects of gene therapy," Grompe said. "If we had that attitude we would have never figured out bone marrow transplants; many people died in those trials. The key is how many other options do you have."

Gene therapy has been used to cure only one disease, an immune system disorder called severe combined immunodeficiency, or SCID. Most people know it as "bubble boy disease." When three children in a French study developed leukemia linked to the virus used in gene therapy, treatment was halted. Now only children with no other alternative are given gene therapy to treat the disease.

The first high-profile death in a gene therapy trial happened in 1999 at the University of Pennsylvania. A young man named Jesse Gelsinger died after his immune system reacted badly to the virus used in the trial.

But some people facing miserable lives and early deaths at the hands of disease may think that taking a chance on developing cancer later is worth the risk, said Ana Iltis, an associate professor at the Center for Health Care Ethics at St. Louis University.

At the very least, patients need to know exactly what risks they face before deciding whether to go through gene therapy, she said.

Gene therapy is a promising technology with frustrating problems, Munson said, adding that once researchers work out the kinks, gene therapy can save many lives.

"I think gene therapy has such significant benefits that the problems it faces, though complicated, shouldn't be enough to stop it," he said. "I don't think this is the end of gene therapy at all. It's just another problem that needs to be examined and resolved."