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Mouse Transplant Models for Evaluating the Oncogenic Risk of a Self-Inactivating XSCID Lentiviral Vector

Hematopoietic stem cell gene therapy requires the use of integrating retroviral vectors in order to stably transmit a therapeutic gene to mature blood cells. Human clinical trials have shown that some vector integration events lead to disrupted regulation of proto-oncogenes resulting in disordered h...

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Autores principales: Zhou, Sheng, Ma, Zhijun, Lu, Taihe, Janke, Laura, Gray, John T., Sorrentino, Brian P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633865/
https://www.ncbi.nlm.nih.gov/pubmed/23626802
http://dx.doi.org/10.1371/journal.pone.0062333
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author Zhou, Sheng
Ma, Zhijun
Lu, Taihe
Janke, Laura
Gray, John T.
Sorrentino, Brian P.
author_facet Zhou, Sheng
Ma, Zhijun
Lu, Taihe
Janke, Laura
Gray, John T.
Sorrentino, Brian P.
author_sort Zhou, Sheng
collection PubMed
description Hematopoietic stem cell gene therapy requires the use of integrating retroviral vectors in order to stably transmit a therapeutic gene to mature blood cells. Human clinical trials have shown that some vector integration events lead to disrupted regulation of proto-oncogenes resulting in disordered hematopoiesis including T-cell leukemia. Newer vectors have been designed to decrease the incidence of these adverse events but require appropriate pre-clinical assays to demonstrate safety. We have used two distinct mouse serial transplant assays to evaluate the safety of a self-inactivating lentiviral vector intended for use in X-linked severe combined immunodeficiency (XSCID) gene therapy trials. These experiments entailed 28 months of total follow-up and included 386 mice. There were no cases in which the XSCID lentiviral vector clearly caused hematopoietic malignancies, although a single case of B cell malignancy was observed that contained the lentiviral vector as a likely passenger event. In contrast, a SFFV-DsRed γ-retroviral vector resulted in clonal transformation events in multiple secondary recipients. Non-specific pathology not related to vector insertions was noted including T cell leukemias arising from irradiated recipient cells. Overall, this comprehensive study of mouse transplant safety assays demonstrate the relative safety of the XSCID lentiviral vector but also highlight the limitations of these assays.
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spelling pubmed-36338652013-04-26 Mouse Transplant Models for Evaluating the Oncogenic Risk of a Self-Inactivating XSCID Lentiviral Vector Zhou, Sheng Ma, Zhijun Lu, Taihe Janke, Laura Gray, John T. Sorrentino, Brian P. PLoS One Research Article Hematopoietic stem cell gene therapy requires the use of integrating retroviral vectors in order to stably transmit a therapeutic gene to mature blood cells. Human clinical trials have shown that some vector integration events lead to disrupted regulation of proto-oncogenes resulting in disordered hematopoiesis including T-cell leukemia. Newer vectors have been designed to decrease the incidence of these adverse events but require appropriate pre-clinical assays to demonstrate safety. We have used two distinct mouse serial transplant assays to evaluate the safety of a self-inactivating lentiviral vector intended for use in X-linked severe combined immunodeficiency (XSCID) gene therapy trials. These experiments entailed 28 months of total follow-up and included 386 mice. There were no cases in which the XSCID lentiviral vector clearly caused hematopoietic malignancies, although a single case of B cell malignancy was observed that contained the lentiviral vector as a likely passenger event. In contrast, a SFFV-DsRed γ-retroviral vector resulted in clonal transformation events in multiple secondary recipients. Non-specific pathology not related to vector insertions was noted including T cell leukemias arising from irradiated recipient cells. Overall, this comprehensive study of mouse transplant safety assays demonstrate the relative safety of the XSCID lentiviral vector but also highlight the limitations of these assays. Public Library of Science 2013-04-23 /pmc/articles/PMC3633865/ /pubmed/23626802 http://dx.doi.org/10.1371/journal.pone.0062333 Text en © 2013 Zhou et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zhou, Sheng
Ma, Zhijun
Lu, Taihe
Janke, Laura
Gray, John T.
Sorrentino, Brian P.
Mouse Transplant Models for Evaluating the Oncogenic Risk of a Self-Inactivating XSCID Lentiviral Vector
title Mouse Transplant Models for Evaluating the Oncogenic Risk of a Self-Inactivating XSCID Lentiviral Vector
title_full Mouse Transplant Models for Evaluating the Oncogenic Risk of a Self-Inactivating XSCID Lentiviral Vector
title_fullStr Mouse Transplant Models for Evaluating the Oncogenic Risk of a Self-Inactivating XSCID Lentiviral Vector
title_full_unstemmed Mouse Transplant Models for Evaluating the Oncogenic Risk of a Self-Inactivating XSCID Lentiviral Vector
title_short Mouse Transplant Models for Evaluating the Oncogenic Risk of a Self-Inactivating XSCID Lentiviral Vector
title_sort mouse transplant models for evaluating the oncogenic risk of a self-inactivating xscid lentiviral vector
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633865/
https://www.ncbi.nlm.nih.gov/pubmed/23626802
http://dx.doi.org/10.1371/journal.pone.0062333
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