Washington

Doctors at Stanford treat a haemophiliac in a gene-therapy trial — but how safe is the procedure? Credit: M. KAY

The troubled field of gene therapy was dealt a fresh blow this week, after a study suggested that modified viruses used in some trials might cause health problems.

The study, led by geneticist Mark Kay at Stanford University, California, examined a modified virus used in gene-therapy trials to treat haemophilia and cystic fibrosis. It revealed that the virus has the potential to cause the same problems that led to cancer in an unrelated gene-therapy trial last year.

In gene therapy, doctors use a gutted virus as a 'vector' to transfer corrective genes into a patient's cells. But if the vector stitches itself into a cell's genes, it can cause the cell to mutate and become cancerous. This was demonstrated last year, when two children who had gene therapy for severe combined immunodeficiency disease (SCID) developed leukaemia (see Nature 419, 545–546; 200210.1038/419545a).

Scientists are still trying to establish exactly why the SCID patients developed cancer, and will discuss the trial at this week's meeting of the American Society of Gene Therapy in Washington DC. But most agree that gene therapy was the cause.

Kay's study focused on a vector made from an adeno-associated virus — an organism that does not cause disease in people, but which can be engineered to infect human cells. In a paper published online on 1 June (H. Nakai et al. Nature Genet. doi:10.1038/ng1179; 2003), Kay and his colleagues show that the vector used in the haemophilia and cystic fibrosis trials integrates itself more often into genes than it does into regions of DNA that do not contain genes. The finding suggests that the vector could potentially cause the sort of cellular defects that led to cancer in the SCID patients.

But researchers caution that the vector used in the SCID trials, which was based on a retrovirus, is very different from the adeno-associated vector. For instance, retroviruses must insert themselves into human DNA to work, but adeno-associated viral vectors integrate themselves into the genome much less often.

“Adeno-associated vectors clearly have a better safety profile than retroviral vectors,” says David Russell, a geneticist at the University of Washington in Seattle. “But we really can't say yet that adeno-associated vectors won't cause cancer.”

Kay's team, which is running a gene-therapy trial for haemophilia, tracked the adeno-associated viral vectors in mice. They extracted liver cells whose DNA contained the vector and then sequenced the DNA around the vector. They then analysed the sequences to see whether they matched a known gene. The team found that 72% of the time, the vector had interrupted a gene. Had it inserted itself randomly, the vector would have interrupted a gene no more than 40% of the time.

Last August, Frederic Bushman and his colleagues at the Salk Institute for Biological Sciences in La Jolla, California, suggested that retroviruses also insert themselves into genes more often than into other regions of DNA (A. R. Schroder et al. Cell 110, 521–529; 2002).

Such results are leading researchers to seek better ways to target vectors to specific regions of DNA, and to develop vectors that don't integrate into DNA at all. But in the meantime, Kay says that he has taken numerous precautions to protect the 14 haemophiliacs he has treated.

“I don't think we need to modify anything at this point,” Kay says. “But this is a risk we'll have to address before the vector is in widespread use.”