Among the greatest traumas for gene transfer was the development of leukemias in several children participating in trials using retroviral vectors against X-linked Severe Combined Immune Deficiency (X-SCID– also known as “bubble boy syndrome”). About 20 or so children have had their immune systems fully restored by this gene transfer strategy. Tragically, however, five children in two X-SCID studies (one in Paris, the other, London) developed T-cell leukemias that were causally linked to the gene transfer approach.
In the September 2008 issue of Journal of Clinical Investigation, Salima Hacein-Bey Abina and 28 other authors characterize the molecular nature of four of the adverse events, and report the outcome. Before this article, it was known that one of the children died. This article now reports that the other three children have “sustained remission” after chemotherapy.
The authors report that the vector inserted itself at the same genetic locus (LMO2) in 3 of the 4 cases. In one case, vector inserted at a different genetic locus (CCND2); in another, vector inserted itself at LMO2 as well as a second locus, BMI1. This suggests that LMO2 disruption is not the only path to causing cancer for this vector. One other finding stood out. Since the first leukemia was detected, many have speculated that the cancer was partly caused by the gene (rather than just the vector). However, the authors present evidence that the gene was expressed at normal levels in the children who developed leukemia. This lends support to the theory that the leukemias were not caused by the gene, but rather by some combination of the vector, the cell types used, and perhaps some characteristic of the underlying disease. (photo credit: concretecandy, boy in the bubbles, 2006)