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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 leukem...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9932294/ https://www.ncbi.nlm.nih.gov/pubmed/36816757 http://dx.doi.org/10.1016/j.omtm.2023.01.003 |
Sumario: | 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. |
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