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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...

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Autores principales: Saleh, Amr H., Rothe, Michael, Barber, Dwayne L., McKillop, William M., Fraser, Graeme, Morel, Chantal F., Schambach, Axel, Auray-Blais, Christiane, West, Michael L., Khan, Aneal, Fowler, Daniel H., Rupar, C. Anthony, Foley, Ronan, Medin, Jeffrey A., Keating, Armand
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2023
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
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author Saleh, Amr H.
Rothe, Michael
Barber, Dwayne L.
McKillop, William M.
Fraser, Graeme
Morel, Chantal F.
Schambach, Axel
Auray-Blais, Christiane
West, Michael L.
Khan, Aneal
Fowler, Daniel H.
Rupar, C. Anthony
Foley, Ronan
Medin, Jeffrey A.
Keating, Armand
author_facet Saleh, Amr H.
Rothe, Michael
Barber, Dwayne L.
McKillop, William M.
Fraser, Graeme
Morel, Chantal F.
Schambach, Axel
Auray-Blais, Christiane
West, Michael L.
Khan, Aneal
Fowler, Daniel H.
Rupar, C. Anthony
Foley, Ronan
Medin, Jeffrey A.
Keating, Armand
author_sort Saleh, Amr H.
collection PubMed
description 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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spelling pubmed-99322942023-02-17 Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease Saleh, Amr H. Rothe, Michael Barber, Dwayne L. McKillop, William M. Fraser, Graeme Morel, Chantal F. Schambach, Axel Auray-Blais, Christiane West, Michael L. Khan, Aneal Fowler, Daniel H. Rupar, C. Anthony Foley, Ronan Medin, Jeffrey A. Keating, Armand Mol Ther Methods Clin Dev Original Article 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. American Society of Gene & Cell Therapy 2023-01-18 /pmc/articles/PMC9932294/ /pubmed/36816757 http://dx.doi.org/10.1016/j.omtm.2023.01.003 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Saleh, Amr H.
Rothe, Michael
Barber, Dwayne L.
McKillop, William M.
Fraser, Graeme
Morel, Chantal F.
Schambach, Axel
Auray-Blais, Christiane
West, Michael L.
Khan, Aneal
Fowler, Daniel H.
Rupar, C. Anthony
Foley, Ronan
Medin, Jeffrey A.
Keating, Armand
Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease
title Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease
title_full Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease
title_fullStr Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease
title_full_unstemmed Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease
title_short Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease
title_sort persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for fabry disease
topic Original Article
url 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
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