Individuals with a number of life-threatening genetic diseases of the immune system have been successfully treated by gene therapy -- that is, they were infused with early precursors of immune cells that had the correct form of the defective gene delivered into them by agents known as retroviral vectors.
However, some patients later developed leukemia. This slowed progress in the field and has led to detailed studies seeking to determine the mechanisms underlying the cause of leukemia and whether other genes that are candidates for gene therapy approaches might pose a similar risk.
A new study, carried out by Hans-Peter Kiem and colleagues, at the Fred Hutchinson Cancer Research Center, Seattle, has now indicated that early precursors of immune cells that had the gene HOXB4 delivered into them by a gammaretroviral vector became leukemic in 2 of 2 dogs and 1 of 2 macaques.
In vitro analysis established a clear link between HOXB4 expression and leukemia, leading the authors to conclude that the use of HOXB4-based gene therapy would probably carry a high risk of leukemia and that extreme caution is needed when considering gene therapy approaches.
The need for caution is echoed in an accompany commentary by Andre Larochelle and Cynthia E. Dunbar, at the National Institutes of Health, Bethesda, who discuss how important large animal studies, such as those reported by Hans-Peter Kiem and colleagues, are to minimize the risk of adverse events in humans receiving gene therapy in the future.
Journal reference: High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector. Journal of Clinical Investigation. March 20, 2008
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