THERE was more bad news for gene therapists this week. It turns out that another of the favourite viruses in their toolkit has a disturbing habit of landing in or near healthy genes, suggesting gene disruption might be a common problem in gene therapy.
鈥淲hat this means for human trials must be assessed on a disease-by-disease basis,鈥� says Mark Kay of Stanford University in California, who led the study. 鈥淚t raises the bar of risk somewhat. But how much higher it is raised is still unclear.鈥�
The potential dangers of gene therapy hit the headlines recently after 2 out of 11 鈥渂ubble boys鈥� treated in France for the immune disease X-SCID developed a form of leukaemia. In these trials, a mouse retrovirus was used to add a healthy copy of a gene to bone marrow cells. But in some cells the DNA was integrated near Lmo2, a gene that can trigger cancer if disrupted. It turns out that retroviruses, which carry their own protein tools to splice themselves into chromosomes, prefer to integrate near active genes like Lmo2.
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Now Kay鈥檚 team has shown that another group of viruses popular with gene therapists, adeno-associated viruses or AAVs, also tend to integrate near active genes. The team injected AAVs into mouse livers and examined the sites of integration. The particular kind of AAV they studied rarely integrates, and only with the help of the cell鈥檚 own proteins. Even so, of the 29 integrations they examined, 72 per cent were in genes rather than junk DNA, and at least 20 of these genes appeared to be active (Nature Genetics, DOI: 10.1038/ng1179).
It is thought the particular gene added in the X-SCID trial contributed to the high rate of cancer. But if active genes turn out to be natural hot spots for DNA to be inserted, the risks of many other kinds of gene therapy may be higher than thought.
鈥淚t鈥檚 a healthy development that the community realises that there are basic scientific issues that still need to be addressed,鈥� says Philip Noguchi, head of gene therapy issues at the US Food and Drug Administration. But he and Kay think that the benefits still outweigh the risks in most gene therapy trials.