NUMEROUS gene therapy trials have been put on hold after a second child in a French trial developed a leukaemia-like disease. In both the affected children, the added gene landed in the wrong place, turning on a gene that increases the chances of getting cancer.
The bad news is that this may happen far more often than thought. But if the researcher analysing the cases is right, the risks may be due to the nature of the gene added in this trial and the timing of the treatment, rather than the method of adding genes with retroviruses. If confirmed, this work might help persuade the FDA to resume some of the 27 gene therapy trials using retroviruses in the US put on hold last week.
Since 1999, Alain Fischer鈥檚 team at the Necker Hospital in Paris has used gene therapy to treat 11 boys with X-linked severe combined immunodeficiency (X-SCID), which affects those born with a faulty copy of a gene on the X chromosome called gamma c. A genetically engineered retrovirus is used to permanently insert a normal copy of gamma c into bone marrow cells taken from the boys. When the modified cells are put back into their bodies, they divide and create a normal immune system.
Advertisement
But in two boys, some modified white blood cells are multiplying out of control. The FDA halted three X-SCID gene therapy trials last October when the first case was reported. A team at Great Ormond Street Hospital in London has now suspended its trial after the latest case, even though all five children that have been treated so far are healthy. 鈥淲e鈥檝e decided not to do the procedure on any new patients till we鈥檙e clear about what鈥檚 going on,鈥� says a spokesman.
DNA analyses by Christof von Kalle of the Children鈥檚 Hospital Research Foundation in Cincinnati, Ohio, and Freiburg University in Germany have shown that in both cases, the retrovirus inserted the normal copy of gamma c in or near a gene called Lmo2, turning it on permanently. Lmo2 is a 鈥渕aster switch鈥� for early blood formation and the growth of blood vessels, but it can contribute to cancer when it is switched on all the time.
Theoretically the retrovirus could insert the gene anywhere in our genome, but von Kalle鈥檚 findings suggest the chances of it landing near Lmo2 are far higher than thought. 鈥淚t鈥檚 the most prominent insertion site we see by far,鈥� he says. 鈥淥ur working hypothesis is that about 1 in 100,000 white blood cells could be carrying the insertion next to Lmo2.鈥� That might sound low, but during gene therapy about a million bone marrow cells are modified, so the chances of a child getting cells with an insertion near Lmo2 are high.
The reason, von Kalle thinks, is that Lmo2 is switched on in bone marrow cells at the stage in development when the therapy is applied. And when a gene is 鈥渙n鈥�, the DNA helix in the region is unwound and is far more accessible to retroviruses.
However, activating Lmo2 alone should not be enough to cause cancer. The additional factor could be gamma c itself, he says, which plays a critical role in the multiplication of immune cells.
If the problem does prove specific to therapies involving growth-related genes such as gamma c, gene therapists hoping to treat other inherited conditions will be relieved. But the future for X-SCID gene therapy is unclear. There is a small possibility that the problem is specific to the French trial, von Kalle says, as the team in London used a slightly different method.
A key task now is to check the white blood cells in the other patients. 鈥淲e certainly hope no other patients will be affected, but if there is a remote chance they are, we need to find out early,鈥� von Kalle says.
The two affected children are responding well to chemotherapy. But a big worry is that that the chemotherapy will kill all the modified cells, rather than just the cancerous ones. Then the boys will lose their immune systems and be back to square one.
The standard treatment for X-SCID boys is a bone marrow transplant from a matched donor. But suitable donors cannot always be found, which is why doctors turned to gene therapy in the first place.