ArticleMolecular therapy : the journal of the American Society of Gene Therapy2009
A novel model of SCID-X1 reconstitution reveals predisposition to retrovirus-induced lymphoma but no evidence of gammaC gene oncogenicity.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 16 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 28 citations in OpenAlex.
- Thymocyte self-renewal and oncogenic risk in immunodeficient mouse models: relevance for human gene therapy clinical trials targeting haematopoietic stem cell populations?Mammalian genome : official journal of the International Mammalian Genome Society · 2018Review
- Evolving Gene Therapy in Primary Immunodeficiency.Molecular therapy : the journal of the American Society of Gene Therapy · 2017Review
- Limiting Thymic Precursor Supply Increases the Risk of Lymphoid Malignancy in Murine X-Linked Severe Combined Immunodeficiency.Molecular therapy. Nucleic acids · 2017Article
- Inflammatory and anti-inflammatory states of adipose tissue in transgenic mice bearing a single TCR.International immunology · 2017Article
- Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?Human gene therapy · 2016Review
- Article
- Lentiviral vectors for the treatment of primary immunodeficiencies.Journal of inherited metabolic disease · 2014Review
- Concise review: lessons learned from clinical trials of gene therapy in monogenic immunodeficiency diseases.Stem cells translational medicine · 2014Review
- Insertional mutagenesis and deep profiling reveals gene hierarchies and a Myc/p53-dependent bottleneck in lymphomagenesis.PLoS genetics · 2014Article
- Review
- Evaluating risks of insertional mutagenesis by DNA transposons in gene therapy.Translational research : the journal of laboratory and clinical medicine · 2013Review
- Mouse transplant models for evaluating the oncogenic risk of a self-inactivating XSCID lentiviral vector.PloS one · 2013Article
- Correction of murine SCID-X1 by lentiviral gene therapy using a codon-optimized IL2RG gene and minimal pretransplant conditioning.Molecular therapy : the journal of the American Society of Gene Therapy · 2011Article
- Lymphomagenesis in SCID-X1 mice following lentivirus-mediated phenotype correction independent of insertional mutagenesis and gammac overexpression.Molecular therapy : the journal of the American Society of Gene Therapy · 2010Article
- Assessing the risk of T-cell malignancies in mouse models of SCID-X1.Molecular therapy : the journal of the American Society of Gene Therapy · 2010Article
- A transposon and transposase system for human application.Molecular therapy : the journal of the American Society of Gene Therapy · 2010Review
Corrections and comments
- Erratum issuedPhilbey, Adrain [corrected to Philbey, Adrian]; Thrasher, Adrain J [corrected to Thrasher, Adrian J]
Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
The emergence of leukemia following gene transfer to restore common cytokine receptor gamma chain (gammaC) function in X-linked severe combined immunodeficiency (SCID-X1) has raised important questions with respect to gene therapy safety. To explore the risk factors involved, we tested the oncogenic potential of human gammaC in new strains of transgenic mice expressing the gene under the control of the CD2 promoter and locus control region (LCR). These mice demonstrated mildly perturbed T-cell development, with an increased proportion of thymic CD8 cells, but showed no predisposition to tumor development even on highly tumor prone backgrounds or after gamma-retrovirus infection. The human CD2-gammaC transgene rescued T and B-cell development in gammaC(-/-) mice but with an age-related delay, mimicking postnatal reconstitution in SCID-X1 gene therapy subjects. However, we noted that gammaC(-/-) mice are acutely susceptible to murine leukemia virus (MLV) leukemogenesis, and that this trait was not corrected by the gammaC transgene. We conclude that the SCID-X1 phenotype can be corrected safely by stable ectopic expression of gammaC and that the transgene is not significantly oncogenic when expressed in this context. However, an underlying predisposition conferred by the SCID-X1 background appears to collaborate with insertional mutagenesis to increase the risk of tumor development.
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Registered trials
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.