American Society of Gene Therapy (ASGT) ad hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells

In summary, this review of findings in murine and large animal models and in human clinical trials indicates that the development of leukemia in the XSCID subjects was relatively unprecedented and not predicted by preclinical studies. No SAEs related to retroviral vectors were observed, except for a single report in a murine model and the two cases in the XSCID trial. However, in contrast to the very high number of gene-containing cells seen in the XSCID studies (and the Italian trial for ADA deficiency), most of the other clinical studies have been characterized by very low numbers of gene-containing cells in circulation (<1-2 years) and a lack of long-term persistence. Many subjects in the gene marking studies were patients with advanced malignant disease (undergoing therapeutic hematopoietic stem cell transplantation) to which they succumbed within months to a few years of participation in the gene transfer trial. Most treatments for genetic diseases were done without any cytoreductive therapy, and thus engraftment of gene-containing cells was in very low numbers. Thus, the lack of SAEs in these studies cannot be used to support the general safety of retroviral-mediated gene transfer to HSCs. One cannot make conclusions about the safety of gene therapy when there is not significant gene transfer to the relevant target cells. It is possible that the amount of gene transfer to HSCs in these studies was higher than detected by gene marking of PBCs, and the absence of lymphoproliferation indicates that this is not necessarily a problem. The few exceptional studies that did show more long-term persistence of gene-marked cells did not have any cases of leukemia or other complications.