ArticleThe Journal of clinical investigation2003
Methylguanine methyltransferase-mediated in vivo selection and chemoprotection of allogeneic stem cells in a large-animal model.
Article in The Journal of clinical investigation, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 118 citations in OpenAlex.
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- A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas.Scientific reports · 2021Article
- In Vivo HSC Gene Therapy Using a Bi-modular HDAd5/35++ Vector Cures Sickle Cell Disease in a Mouse Model.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Curative in vivo hematopoietic stem cell gene therapy of murine thalassemia using large regulatory elements.JCI insight · 2020Article
- Adenovirus vectors in hematopoietic stem cell genome editing.FEBS letters · 2019Review
- In vivo hematopoietic stem cell gene therapy ameliorates murine thalassemia intermedia.The Journal of clinical investigation · 2019Article
- Improving the Transduction of Bone Marrow-Derived Cells with an Integrase-Defective Lentiviral Vector.Human gene therapy methods · 2018Article
- Mechanistic Models Predict Efficacy of CCR5-Deficient Stem Cell Transplants in HIV Patient Populations.CPT: pharmacometrics & systems pharmacology · 2016Article
- 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
- (211)Astatine-Conjugated Monoclonal CD45 Antibody-Based Nonmyeloablative Conditioning for Stem Cell Gene Therapy.Human gene therapy · 2015Article
- Efficiency and safety of O⁶-methylguanine DNA methyltransferase (MGMT(P140K))-mediated in vivo selection in a humanized mouse model.Human gene therapy · 2014Article
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
Abstract
Clinical application of gene therapy for genetic and malignant diseases has been limited by inefficient stem cell gene transfer. Here we studied in a clinically relevant canine model whether genetic chemoprotection mediated by a mutant of the DNA-repair enzyme methylguanine methyltransferase could circumvent this limitation. We hypothesized that genetic chemoprotection might also be used to enhance allogeneic stem cell transplantation, and thus we evaluated methylguanine methyltransferase-mediated chemoprotection in an allogeneic setting. We demonstrate that gene-modified allogeneic canine CD34+ cells can engraft even after low-dose total body irradiation conditioning. We also show that cytotoxic drug treatment produced a significant and sustained multilineage increase in gene-modified repopulating cells. Marking in granulocytes rose to levels of up to 98%, the highest in vivo marking reported to date to our knowledge in any large-animal or human study. Increases in transgene-expressing cells after in vivo selection provided protection from chemotherapy-induced myelosuppression, and proviral integration site analysis demonstrated the protection of multiple repopulating clones. Drug treatment also resulted in an increase in donor chimerism. These data demonstrate that durable, therapeutically relevant in vivo selection and chemoprotection of gene-modified cells can be achieved in a large-animal model and suggest that chemoprotection can also be used to enhance allogeneic stem cell transplantation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.