Occurrence of leukaemia following gene therapy of X-linked SCID View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2003-07

AUTHORS

Donald B. Kohn, Michel Sadelain, Joseph C. Glorioso

ABSTRACT

Key PointsGene therapy for blood-cell diseases can be performed with retroviral vectors that insert into the genome of haematopoietic stem cells.A recent trial of gene therapy for infants with X-linked severe combined immune deficiency (XSCID) successfully restored the immune systems of most subjects.Two subjects developed T-cell leukaemia more than 2 years after gene therapy commenced. This cancer seems to be caused by retroviral-vector activation of a cellular oncogene at the site of integration, a process known as 'insertional oncogenesis'.The complication of leukaemia has not occurred in any other clinical trial, nor in any large animal model that used retroviral vectors to modify haematopoietic stem cells. Leukaemia has been linked to vector integration in only one mouse study using this approach.Multiple factors could have contributed to the development of leukaemia in the patients involved in this trial. These include the high level of engraftment and expansion of the genetically modified cells, unique properties of the haematopoietic stem and progenitor cells in bone marrow of X-linked SCID patients, the immune deficiency of the X-linked SCID patients and/or the transferred gene itself.Further use of current gene-transfer methods for the treatment of SCID poses an ethical dilemma in the consideration of the complex benefits and risks.It might be possible to develop retroviral vectors or other gene-therapy methods that are less likely to lead to insertional oncogenesis and still retain the therapeutic benefits. The use of tissue-specific, regulated transcription units should, in principle, diminish the risk of proto-oncogene transactivation. More... »

PAGES

477-488

References to SciGraph publications

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  • Journal

    TITLE

    Nature Reviews Cancer

    ISSUE

    7

    VOLUME

    3

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nrc1122

    DOI

    http://dx.doi.org/10.1038/nrc1122

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1010076917

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/12835668


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