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

Mol Ther Methods Clin Dev. 2023 Jan 18;28:262-271. doi: 10.1016/j.omtm.2023.01.003. eCollection 2023 Mar 9.


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.

Keywords: Fabry disease; clinical trial; gene therapy; lentiviral integration; lentiviral safety.