THE finger of suspicion for the leukaemia that struck a young French boy receiving gene therapy is pointing squarely at the retrovirus used to treat his condition.
Alain Fischer and his colleagues at the Necker Hospital in Paris worked with a retrovirus called the murine leukaemia virus (MLV). To prevent the virus replicating in the body, they stripped out its reproductive genes. Then they used the modified virus to ferry a healthy copy of the boy鈥檚 defective gene into cells taken from his bone marrow. The MLV infected the cells, dropping itself and the healthy gene into the boy鈥檚 DNA.
However, there is at present no way to control where such viruses 鈥渓and鈥�. And in at least one batch of stem cells given to the boy, the added DNA ended up inside Lmo2, an oncogene on chromosome 11 that is implicated in leukaemia. The fear is that the virus switched on Lmo2 as well as the added gene (see Diagram).
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If so, the key question is: was this bad luck 鈥� a one-off event 鈥� or something that is likely to recur whenever gene therapists use retroviruses to correct genetic defects?
Nicholas Lemoine of Imperial College in London, who edits the journal Gene Therapy, thinks that it is simply bad luck, but says we desperately need more data in order to understand the risks. The key is to find out how likely it is that retroviruses will land in and activate any of the 300 or so known oncogenes in the human genome. 鈥淭hree thousand individuals have had genes introduced in some way or another,鈥� says Lemoine, 鈥渁nd a substantial number were treated with retroviruses.鈥�
Most of the recipients of retroviruses have been children with an inherited condition called ADA deficiency. It means they can鈥檛 make the enzyme adenosine deaminase, which is vital for immune function. Savio Woo, director of gene therapy and molecular medicine at the Mount Sinai School of Medicine in New York City, reckons that hundreds of patients have received the viruses in the US.
One fear is that MLV may actually prefer to embed itself in genes linked with leukaemia. But that idea is rejected by Adrian Thrasher and Bobby Gaspar, immunologists with the gene therapy team in London at the Institute of Child Health at Great Ormond Street Hospital in London. They say the virus embeds itself in different places in every patient.
Since there are more than 3 billion places where the therapeutic DNA could land, and because only 10 to 100 of the infected bone marrow cells 鈥渢ake鈥� when returned to the patient, the chances of an oncogene being activated in those 10 to 100 hits are slim indeed. But Thrasher is open to the idea there might be some 鈥渉ot spots鈥� where the virus tends to settle. After all, he points out, HIV does show such preferences.
All researchers contacted by New 杏吧原创 agreed that activating a single oncogene is seldom enough to cause cancer. Often, other genes need to be activated as well. Ken Campbell, clinical information officer at Britain鈥檚 Leukaemia Research Fund, says that the young French boy may already have had a genetic predisposition for leukaemia and that the retrovirus simply set the ball rolling.
Whatever the answer, the best solution will be to control where therapeutic genes land. Retroviruses do exist that always embed themselves at the same spot in the genome, for example. But they鈥檙e not as efficient at injecting genes as the those, such as MLV, that integrate unpredictably. Fischer says that it might be possible to add 鈥渋nsulators鈥� to the ends of the MLV genome in the hope of isolating it more fully from the surrounding genome. Another option might be to modify the retrovirus so that it is only able to switch on the added gene.