Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease

The safety and efficacy of lentivirus-mediated gene therapy was recently demonstrated in five male patients with Fabry disease—a rare X-linked lysosomal storage disorder caused by GLA gene mutations that result in multiple end-organ complications. To evaluate the risks of clonal dominance and leukemogenesis, which have been reported in multiple gene therapy trials, we conducted a comprehensive DNA insertion site analysis of peripheral blood samples from the five patients in our gene therapy trial. We found that patients had a polyclonal integration site spectrum and did not find evidence of a dominant clone in any patient. Although we identified vector integrations near proto-oncogenes, these had low percentages of contributions to the overall pool of integrations and did not persist over time. Overall, we show that our trial of lentivirus-mediated gene therapy for Fabry disease did not lead to hematopoietic clonal dominance and likely did not elevate the risk of leukemogenic transformation. [Display omitted] This study by Dr. Armand Keating and colleagues utilized integration site analysis to determine whether lentivirus-transduced hematopoietic cells, used in a Fabry disease gene therapy clinical trial, remain polyclonal. The study shows no evidence of a dominant pre-malignant clone, providing reassuring data on lentivirus-mediated gene therapy safety.