A Serious Adverse Event after Successful Gene Therapy for X-Linked Severe Combined Immunodeficiency

Abstract

We recently reported (April 18 issue) 1 the sustained correction of X-linked severe combined immunodeficiency disease by ex vivo, retrovirally mediated transfer of the g c gene into CD34+ cells in four of five patients with the disease. These results have since been confirmed in four additional patients with typical X-linked severe combined immunodeficiency. Of the first four successfully treated patients, three continue to do well up to 3.6 years after gene therapy, whereas a serious adverse event occurred in the fourth patient. At a routine checkup 30 months after gene therapy, lymphocytosis consisting of a monoclonal population of V g 9/V d 1, g / d T cells of mature phenotype was detected. One proviral integration site was found, located on the short arm of chromosome 11 within the LMO-2 locus, as determined with the use of linearamplification mediated polymerase-chain-reaction analysis. 2 This proviral integration within the LMO-2 locus was associated with aberrant expression of the LMO-2 transcript in the monoclonal T-cell population. Aberrant expression of LMO-2 has been reported in acute lymphoblastic leukemia arising from T cells with a / b receptors, usually with the chromosomal translocation t(11;14). 3 Tests for replicationcompetent retrovirus were repeatedly negative in our patient's lymphocytes. Between 30 and 34 months after gene therapy, the patient's lymphocyte count rose to 300,000 per cubic millimeter, and hepatosplenomegaly developed. Further investigations showed the presence of a t(6;13) translocation, which had not been detected 30 months after the therapy. Treatment with a chemotherapy regimen based on a high-risk protocol for acute lymphocytic leukemia (a protocol of the Dutch Childhood Leukemia Study Group) was initiated and has resulted, to date, in a dramatic reduction in the abnormal cells.

Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice

“…However, in recent X-SCID gene therapy trials several cases of iatrogenic acute lymphoblastic leukaemia were reported after ex vivo retroviral transduction of the bone marrow cells. 3 Detailed molecular and genetic analyses demonstrated integration of the gammaretroviral genome into the regulatory region of the host LMO2 proto-oncogene, directly implicating the vector in the oncogenic process. 4 Concerns have also been raised by several in vivo studies regarding the possibility of pro-oncogenic events arising from recombinant adeno-associated virus (rAAV) vectormediated gene transfer to hepatocytes, concerns that are supported by vector integration site analyses.…”

“…Duration is also of relevance as the incidences of many human tumours increase substantially with longevity. Notably, even the transformation events that occurred after retroviral gene transfer treatment of X-SCID patients did not result in detectable malignancy until 30 months after treatment, 3 despite the fact that haematopoietic stem cells divide readily and frequently, even in the absence of transformation. Furthermore, the cumulative total number of subjects treated so far in the ophthalmic trials is relatively low.…”

Evolving gene therapy approaches for osteosarcoma using viral vectors: Review

“…Next to these tragic events, one of the first success of gene therapy also brought a major tragedy as was reported in 2000 when a group in Paris succeeded in totally correcting Severe Combined Immune Deficiency using a retroviral vector in children, but 2 of the treated children later developed leukemia (49). SCID is characterized by a total lack of T lymphocytes and natural killer cells, which normally defends the body against infections.…”

Gene therapy for optic nerve disease

“…They achieved significant levels of immune reconstitution in all but one of the subjects, 5 but the trial had to be suspended when two patients developed leukaemia. 6,7 Concern about the risk of 'insertional oncogenesis' has led to the suspension of other human gene therapy trials using similar vectors to allow for further analysis of the risk-to-benefit ratio.…”