Challenges in vector and trial design using retroviral vectors for long-term gene correction in hematopoietic stem cell gene therapy.

Over the past two decades, incredible progress has been made using gene therapy for inherited severe immunodeficiency disorders, such as X-linked severe combined immunodeficiency disorder (SCID-X1) and adenosine deaminase deficiency–severe combined immunodeficiency disorder (ADA-SCID).1,2,3 However, for reasons that remain unclear, gene transfer for SCID-X1 has also been associated with some cases of vector-induced leukemia whereas no cases have been seen in the ADA-SCID trials despite the common use of g-retroviral vectors. The first case was reported in a French gene transfer trial for SCID-X1.4 Over the next six years, an additional three cases were reported in that trial and one in a second SCID-X1 trial that enrolled a combined total of 20 subjects.2 Unfortunately, genotoxicity would not remain confined to SCID-X1. Recent reports of insertional mutagenesis leading to myelodysplastic syndrome in a trial for chronic granulomatous disease and a case of leukemia in a trial for Wiskott-Aldrich syndrome (WAS), both of which used g-retroviral vectors, underscored that this type of toxicity can also apply to other disease settings.5,6,7 In all these cases, insertion of the g-retroviral vector near known proto-oncogenes led to enhancer-mediated expression of these proto-oncogenes.