Public Release:  Cancer risk clouds gene cures

New Scientist

DESPITE its spectacular achievements, the first successful form of gene therapy will for now be used only as a last resort due to the risk of cancer. And that's not the only bad news. The latest studies suggest that some other gene therapies using different viruses might also trigger cancer.

The Necker Hospital in Paris pioneered the use of gene therapy to cure the severe inherited immune disease called X-SCID. But two of the 11 boys treated have developed leukaemia. Both these cases appear to be due to the corrective gene being inserted near another gene called Lmo2, which helps control cell growth and can contribute to cancer if turned on at the wrong time (New Scientist, 25 January, p 12).

Calculations by Christof von Kalle of the University of Cincinnati College of Medicine in Ohio suggest that rather than being an extraordinary coincidence the engineered mouse retrovirus used to deliver the gene in the French studymay insert it near Lmo2 about once per 100,000 insertions. Since millions of bone marrow cells are modified and returned to the boys, such insertions may crop up in most if not all of the patients.

The added gene has now turned up near Lmo2 in a third child in the French trial, von Kalle last week told a gene therapy conference in Banff, Canada. Fortunately, the boy shows no signs of leukaemia, suggesting that a further genetic defect may be necessary to trigger uncontrolled growth of the modified cells.

Gene therapists are still hoping that this problem will prove specific to the gene or methods used in the X-SCID therapy. But experiments done by Frederic Bushman of the Salk Institute near San Diego suggests there could also be a potential problem with HIV and other related retroviruses, which many researchers are planning to use in gene therapy.

Bushman infected human cells with the viruses and looked to see where they landed. Last year, he reported that the viruses are more likely to land in genes- especially in active ones- than in the regions between genes.

Now it seems the viruses prefer to land in genes that can trigger cancer if wrongly switched on or off. Of 440 viral insertions into genes, 5 per cent occurred in known "oncogenes", even though these make up only 1.6 per cent of all genes, he told the conference.

"It looks like we're seeing a significant bias in favour of insertion into oncogenes," says Bushman. "This is potentially not the greatest news." However, he stresses that no one yet knows whether these insertions turn oncogenes on or off, or indeed have any effect on them at all.

Despite these findings, most gene therapists remain optimistic. "I don't think this signals the end of the retrovirus [in gene therapy]," says Michel Sadelain of the Sloan-Kettering Cancer Center in New York. "There are things that one can do to reduce the risk." This includes modifying viruses so they insert genes only in specific sites in the genome, or adding self-destruct mechanisms so doctors could kill the altered cells if any went awry, says Sadelain.

In the meantime, an FDA advisory committee last week recommended that 27 suspended gene therapy trials should proceed only if gene therapy is the only option. Similarly, Great Ormond Street Children's Hospital in London will treat X-SCID boys only if "death is otherwise inevitable". The French trial remains on hold.

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New Scientist issue: 15th March 2003

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Bob Holmes

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