Why Gene Therapy Caused Leukemia In Some ‘Boy In The Bubble Syndrome’ Patients
Severe combined immunodeficiency (SCID), sometimes called ‘Boy in the bubble syndrome’, is a genetic disorder in which the patient lacks most types of immune cell. Almost 10 years ago, two independent groups (one in London, United Kingdom, and one in Paris, France) used gene therapy to treat a few infants with the most common form of SCID, SCID-X1, which is caused by mutations in the IL2RG gene.
Although most infants showed dramatic improvement following gene therapy, 4 of the 9 infants that were successfully treated in Paris developed leukemia between 3 and 6 years after the treatment. The groups in London and Paris had used very similar gene therapy approaches and until now it was not clear why leukemia was detected only in some of the infants treated in Paris. However, Adrian Thrasher and colleagues, at the Institute for Child Health, London, now report that 1 of the infants successfully treated in London also developed a form of leukemia known as T cell acute lymphoblastic leukemia (T-ALL).
In the study, Thrasher and colleagues go on to show why that infant developed leukemia. During gene therapy, the correct form of the IL2RG gene and the vector that carried this into the cells integrated into part of the genome that contained a gene known as LMO2 and activated this gene. In combination with other genetic mutations that were not caused by the gene therapy (including activation of the NOTCH1 gene, deletion of the CDKN2A gene locus, and translocation of the TCRb gene into the SIL-TAL1 locus), this caused the development of leukemia.
In a related paper by Salima Hacein-Bey-Abina and colleagues, the researchers in Paris who performed the other gene therapy trial have now identified similar reasons to explain why 2 of the 4 infants that developed leukemia became sick. In one patient, the gene and vector integrated into the part of the genome that contained LMO2 and activated the gene, and in the other patient, the gene and vector integrated into part of the genome that contained a gene known as CCND2 and activated this gene.
In both infants, other genetic mutations not caused by the gene therapy contributed to the development of leukemia and these mutations were very similar to those observed in the patient treated in London (activation of the NOTCH1 gene, deletion of the CDKN2A gene locus, and rearrangement of the SIL-TAL1 locus).
The authors of both studies hope that these data provide insight that will help in the design of future gene therapy protocols to ensure similar efficacy but decreased toxicity.
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- Hacein-Bey-Abina et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. Journal of Clinical Investigation, 2008; DOI: 10.1172/JCI35700