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    Brian P. Sorrentino, MD

    Discovery in "Bubble Boy" disease gene therapy

    St. Jude researchers determine why gene therapy treatment caused leukemia in some severe immune deficiency patients; discovery offers hope for safe treatment.

    Scientists at St. Jude Children's Research Hospital have developed a mouse model of a severe disease of the immune system that helps explain why gene therapy used to treat children with this disease at an institution in Europe caused some of them to develop leukemia. The disease, called X-linked severe combined immunodeficiency (XSCID), is caused by a mutation in a gene called gamma C that prevents the immune system from forming B and T lymphocytes.

    XSCID was made famous by the story of the so-called “Bubble Boy” who lived inside a plastic “bubble” to shield him from infections. In gene therapy for this disease, normal copies of the gamma C gene are inserted into stem cells that later give rise to these lymphocytes. Following the development of leukemia by the patients in France, researchers determined that some of the gamma C genes had inserted themselves into oncogenes—cancer causing genes. This caused the stem cells to multiply uncontrollably and produce leukemia.

    The St. Jude researchers concluded that XSCID itself makes their mouse models—and by extension, children with this disease--particularly susceptible to cancer caused by gene therapy. Specifically, the team found that the population of primitive stem cells that is the target of gene therapy is abnormally large. This increases the chance that gamma C genes that are put into the cells will insert themselves into oncogenes—genes that cause cancer when activated.

    One major implication of this finding is that gene therapy for other forms of genetic blood diseases will pose significantly less risk for causing cancer than was previously thought, according to Brian Sorrentino, MD, director of the St. Jude Experimental Hematology Division and co-director of Transplantation and Gene Therapy. Sorrentino is the senior author of a report on these findings that appears in the August 1 issue of Proceedings of the National Academy of Sciences.

    “Our current findings with this new mouse model offer real hope that we can make gene therapy for X-linked SCID safe as well as effective,” said Yan Shou, PhD, the first author of the paper and the major contributor to this work. Other authors of the paper include Zhijun Ma and Taihe Lu.

    This work was supported in part by the National Heart, Lung, and Blood Institute; a Cancer Center Support Grant; the Assisi Foundation of Memphis; and ALSAC.


    August 2006