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J Inherit Metab Dis. 2017 Jul;40(4):497-517. doi: 10.1007/s10545-017-0053-3. Epub 2017 May 31.

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects.

Author information

1
Genetics and Genomic Medicine Programme, Great Ormond Street Institute of Child Health, University College London, London, UK. j.baruteau@ucl.ac.uk.
2
Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. j.baruteau@ucl.ac.uk.
3
Gene Transfer Technology Group, Institute for Women's Health, University College London, London, UK. j.baruteau@ucl.ac.uk.
4
Gene Transfer Technology Group, Institute for Women's Health, University College London, London, UK.
5
Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
6
Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Institute, Westmead, Australia.
7
Discipline of Child and Adolescent Health, University of Sydney, Sydney, Australia.
8
Genetics and Genomic Medicine Programme, Great Ormond Street Institute of Child Health, University College London, London, UK.
9
Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
10
MRC Laboratory for Molecular Cell Biology, University College London, London, UK.

Abstract

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics.

PMID:
28567541
PMCID:
PMC5500673
DOI:
10.1007/s10545-017-0053-3
[Indexed for MEDLINE]
Free PMC Article

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