ArticleThe Journal of clinical investigation2009
In vivo selection of hematopoietic progenitor cells and temozolomide dose intensification in rhesus macaques through lentiviral transduction with a drug resistance gene.
Article in The Journal of clinical investigation, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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The trial behind it
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Who cites it
35 citing papers in PubMed, 54 citations in OpenAlex.
- Article
- Safe and efficientMolecular therapy. Methods & clinical development · 2022Article
- In vivo hematopoietic stem cell gene therapy ameliorates murine thalassemia intermedia.The Journal of clinical investigation · 2019Article
- Integrating HDAd5/35++ Vectors as a New Platform for HSC Gene Therapy of Hemoglobinopathies.Molecular therapy. Methods & clinical development · 2018Article
- A CombinedMolecular therapy. Methods & clinical development · 2018Article
- Overexpression of NAC1 confers drug resistance via HOXA9 in colorectal carcinoma cells.Molecular medicine reports · 2017Article
- Gene Addition Strategies for β-Thalassemia and Sickle Cell Anemia.Advances in experimental medicine and biology · 2017Review
- Towards in vivo amplification: Overcoming hurdles in the use of hematopoietic stem cells in transplantation and gene therapy.World journal of stem cells · 2015Review
- Foamy viral vector integration sites in SCID-repopulating cells after MGMTP140K-mediated in vivo selection.Gene therapy · 2015Article
- In vivo enrichment of genetically manipulated platelets corrects the murine hemophilic phenotype and induces immune tolerance even using a low multiplicity of infection.Journal of thrombosis and haemostasis : JTH · 2014Article
- Efficiency and safety of O⁶-methylguanine DNA methyltransferase (MGMT(P140K))-mediated in vivo selection in a humanized mouse model.Human gene therapy · 2014Article
- Review
- Efficient selection of genetically modified human T cells using methotrexate-resistant human dihydrofolate reductase.Gene therapy · 2013Article
- Which drug or drug delivery system can change clinical practice for brain tumor therapy?Neuro-oncology · 2013Review
- Genetic modification of mouse bone marrow by lentiviral vector-mediated delivery of hypoxanthine-Guanine phosphoribosyltransferase short hairpin RNA confers chemoprotection against 6-thioguanine cytotoxicity.Transplantation proceedings · 2013Article
- Hematopoietic stem cell gene therapy:assessing the relevance of preclinical models.Seminars in hematology · 2013Review
- F2A sequence linking MGMT(P140K) and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells.Cancer gene therapy · 2012Article
- Chemoselection of allogeneic HSC after murine neonatal transplantation without myeloablation or post-transplant immunosuppression.Molecular therapy : the journal of the American Society of Gene Therapy · 2012Article
- Development of gene therapy for thalassemia.Cold Spring Harbor perspectives in medicine · 2012Review
- Chemoprotection in brain tumor patients: another success for stem cell gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2012Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
Major limitations to gene therapy using HSCs are low gene transfer efficiency and the inability of most therapeutic genes to confer a selective advantage on the gene-corrected cells. One approach to enrich for gene-modified cells in vivo is to include in the retroviral vector a drug resistance gene, such as the P140K mutant of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT*). We transplanted 5 rhesus macaques with CD34+ cells transduced with lentiviral vectors encoding MGMT* and a fluorescent marker, with or without homeobox B4 (HOXB4), a potent stem cell self-renewal gene. Transgene expression and common integration sites in lymphoid and myeloid lineages several months after transplantation confirmed transduction of long-term repopulating HSCs. However, all animals showed only a transient increase in gene-marked lymphoid and myeloid cells after O6-benzylguanine (BG) and temozolomide (TMZ) administration. In 1 animal, cells transduced with MGMT* lentiviral vectors were protected and expanded after multiple courses of BG/TMZ, providing a substantial increase in the maximum tolerated dose of TMZ. Additional cycles of chemotherapy using 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) resulted in similar increases in gene marking levels, but caused high levels of nonhematopoietic toxicity. Inclusion of HOXB4 in the MGMT* vectors resulted in no substantial increase in gene marking or HSC amplification after chemotherapy treatment. Our data therefore suggest that lentivirally mediated gene transfer in transplanted HSCs can provide in vivo chemoprotection of progenitor cells, although selection of long-term repopulating HSCs was not seen.
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