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Discovery In "Bubble Boy" Disease Gene Therapy

ren to develop full immune systems. However, three of the patients eventually developed leukemia, an event that caused the field of gene therapy to reconsider the safety of this approach.

Researchers later determined that the gamma C gene added to the stem cells had inserted itself into oncogenes (cancer-causing genes). The genetic on-switch that was part of the gamma C gene had turned on the oncogenes in the blood cells and caused them to multiply uncontrollably, causing leukemia. To study this complication of gene therapy, Sorrentino's group developed a mouse model that lacked the gene for gamma C (gamma C-/-) as well as Arf (Arf -/-). Arf is an important "tumor-suppressor" gene that forces cells that multiply abnormally fast to commit suicide. By using a mouse lacking Arf, the team ensured that leukemia caused by gene therapy in this model would not be suppressed by the gene's activity.

The researchers removed bone marrow stem cells from these new mouse models (Arf -/- gamma C -/- ) and inserted gamma C into them using specially modified viruses called vectors. The researchers then infused the treated cells back into the XSCID mice. The gene therapy cured the genetic disease, but 13 out of 15 of the treated XSCID mice went on to develop leukemia, the researchers reported. The team removed leukemic cells from mice that developed cancer and found that gamma C genes had inserted themselves into a variety of oncogenes.

In another experiment, the St. Jude investigators used mouse models that lacked Arf but had normal gamma C genes and therefore did not have XSCID. The team used this model to determine whether gene therapy would cause cancer even if a mouse model did not have XSCID. The researchers found that the rate of cancer development in non-XSCID mice getting gene therapy was significantly lower than among mice that had XSCID. "This finding suggests the presence of XSCID disease is a strong risk factor for developing leukemia fr
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