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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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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. |
format | Online Article Text |
id | pubmed-3633865 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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