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Delivering efficient liver-directed AAV-mediated gene therapy.

Baruteau, J; Waddington, SN; Alexander, IE; Gissen, P; (2017) Delivering efficient liver-directed AAV-mediated gene therapy. Gene Therapy , 24 (5) pp. 263-264. 10.1038/gt.2016.90. Green open access

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Abstract

Adeno-associated virus vectors (AAV) have become the leading technology for liver-directed gene therapy. After the pioneering trials using AAV2 and AAV8 to treat haemophilia B, D’Avola et al. recently reported the first-in-human clinical trial of adeno-associated virus vector serotype 5 (AAV5) in acute intermittent porphyria (AIP). Treatment was reported as safe, but the main surrogate biomarkers of AIP, porphobilinogen (PBG) and delta-aminolevulinate (ALA) were unchanged. This lack of efficacy contrasts with results from the haemophilia B trial using AAV8 capsid by Nathwani et al., which showed a significant and long-lasting improvement of the clinical phenotype. Haemophilia B is an amenable target for successful gene therapy as raising expression of plasma factor IX (FIX) level above 1% can modify the phenotype from severe to moderate. Development of a variety of capsids for clinical application is useful to overcome pre-existing neutralising antibodies. The differences in cell-specific transduction by different AAV serotypes are primarily owing to specificities in cellular uptake or post cell-entry processing. Indeed AAV5 presents several theoretical advantages as an alternative capsid to AAV8 for liver-directed gene therapy: suitable liver tropism, less off-target biodistribution, low seroprevalence in humans and minimal cross-reactivity with other serotypes.

Type: Article
Title: Delivering efficient liver-directed AAV-mediated gene therapy.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/gt.2016.90
Publisher version: http://dx.doi.org/10.1038/gt.2016.90
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health > Maternal and Fetal Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1535479
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