Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.564826
Title: A hybrid lentivirus-transposon vector for safer gene therapy
Author: Vink, C. A.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2010
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Abstract:
Gene therapy vectors based on the HIV-1 lentivirus are an attractive option for clinical applications because they enter a broad range of target cells efficiently and deliver stable gene expression through integration into host chromosomes. However, lentiviral vectors are known to integrate preferentially within actively transcribing genes. Leukaemia-like expansions observed in gene therapy trials using gammaretroviral vectors and are thought to have been caused by disruption of host proto-oncogenes at or close to the vector integration site, and the safety of these vectors may be related to the pattern of vector integration with respect to genes. The safety of integrating gammaretroviral and lentiviral vectors is therefore a significant concern with respect to their use in gene therapy. In this study, this problem was addressed by developing a novel hybrid vector which combines the efficient cell and nuclear entry properties of lentiviral vectors with chromosomal integration by the Sleeping Beauty transposase. Unlike the HIV-1 integrase enyme, Sleeping Beauty transposase does not exhibit a preference for integration within active genes. Nonintegrating lentiviral vectors were developed to carry Sleeping Beauty transposon and transposase expression cassettes. These were able to deliver transient transposase expression to target cells, and episomal lentiviral DNA was found to be a suitable substrate for integration by Sleeping Beauty transposase. Importantly, integration with this novel vector was found to occur significantly less frequently within active genes than a standard lentiviral vector. Finally, it was shown that the transposase protein can be incorporated into lentiviral vector particles in a manner analogous to HIV-1 integrase. The development of vectors with safer integration patterns may lead to better clinical outcomes for patients treated with gene therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.564826  DOI: Not available
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