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Delivering efficient liver-directed AAV-mediated gene therapy

Gene Therapy volume 24, pages 263–264 (2017)Cite this article

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Adeno-associated virus vectors (AAV) have become the leading technology for liver-directed gene therapy.1 After the pioneering trials using AAV2(ref. 2) and AAV8(ref. 3) to treat haemophilia B, D’Avola et al.4 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.,3 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.3 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,5 low seroprevalence in humans and minimal cross-reactivity with other serotypes.6

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Acknowledgements

JB is supported by a Clinical Starter Research Grant from Great Ormond Street Hospital for Children Charity.

Author contributions

JB wrote the manuscript. SNW, IEA and PG contributed and revised the manuscript. All authors read and approved the final manuscript.

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Author notes

  1. S N Waddington, I E Alexander and P Gissen: Co-authors.

Authors and Affiliations

  1. Genetics and Genomic Medicine Programme, Great Ormond Street Institute of Child Health, University College London, London, UK

    J Baruteau & P Gissen

  2. Department of Metabolic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

    J Baruteau & P Gissen

  3. Maternal and Fetal Medicine, Gene Transfer Technology Group, Institute for Women’s Health, University College London, London, UK

    J Baruteau & S N Waddington

  4. Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witswatersrand, Johannesburg, South Africa

    S N Waddington

  5. Gene Therapy Research Unit, The Children’s Hospital at Westmead and Children’s Medical Research Institute, Sydney, New South Wales, Australia

    I E Alexander

  6. Discipline of Child and Adolescent Health, The University of Sydney, Sydney, New South Wales, Australia

    I E Alexander

  7. MRC Laboratory for Molecular Biology, University College London, London, UK

    P Gissen

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  1. J Baruteau
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Correspondence to J Baruteau.

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Baruteau, J., Waddington, S., Alexander, I. et al. Delivering efficient liver-directed AAV-mediated gene therapy. Gene Ther 24, 263–264 (2017). https://doi.org/10.1038/gt.2016.90

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