Human Gene Therapy - April 2023 - 273

RESEARCH ARTICLES
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Assessment of Pre-Clinical Liver Models Based on Their Ability
to Predict the Liver-Tropism of Adeno-Associated Virus Vectors
Adrian Westhaus,1,2,{ Marti Cabanes-Creus,1,{ Kimberley L. Dilworth,1 Erhua Zhu,3 David Salas Go´ mez,4
Renina G. Navarro,1 Anais K. Amaya,3 Suzanne Scott,1,3,5 Magdalena Kwiatek,6 Alexandra L. McCorkindale,7
Tara E. Hayman,7 Silke Frahm,8 Dany P. Perocheau,9-11 Bang Manh Tran,12 Elizabeth Vincan,12-14
Sharon L. Wong,15,16 Shafagh A. Waters,15-17 Georgina E. Riddiough,12,18 Marcos V. Perini,18
Laurence O.W. Wilson,5,19 Julien Baruteau,9-11 Sebastian Diecke,8 Gloria Gonza´ lez-Aseguinolaza,4
Giorgia Santilli,2 Adrian J. Thrasher,2 Ian E. Alexander,3,20 and Leszek Lisowski1,21,22,*
1Translational Vectorology Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, Australia;
2Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; 3Gene Therapy Research Unit, Children's Medical Research
Institute and Sydney Children's Hospitals Network, Faculty ofMedicine and Health, The University ofSydney, Westmead, Australia; 4Gene Therapy and Regulation of
Gene Expression Department, IdiSNA, Instituto de Investigacio´n Sanitaria de Navarra, Universidadde Navarra, CIMA, Pamplona, Spain; 5Australian e-Health Research
Centre, Commonwealth Scientific and Industrial Research Organisation, Sydney, Australia; 6Military Institute of Hygiene and Epidemiology, The Biological Threats
Identification and Countermeasure Centre, Puławy, Poland; 7Inventia Life Science Pty Ltd., Sydney, Australia; 8Stem Cell Technology Platform, Max Delbru¨ck
Centrum for Molecular Medicine, Berlin, Germany; 9Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College
London, London, United Kingdom; 10Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom;
11National Institute of Health Research Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom; 12Department of Infectious Diseases,
Melbourne Medical School, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; 13Victorian Infectious
Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; 14Curtin Medical School,
Curtin University, Perth, Australia; 15Molecularand Integrative Cystic Fibrosis (miCF) Research Centre, University ofNewSouth Wales andSydney Children's Hospital,
Sydney, Australia; 16School of Biomedical Sciences, Faculty of Medicine, University ofNew South Wales, Sydney, Australia; 17Department of Respiratory Medicine,
Sydney Children's Hospital, Faculty of Medicine, University ofNew South Wales, Sydney, Australia; 18Department of Surgery, Austin Health Precinct, The University
of Melbourne, Austin Health, Heidelberg, Australia; 19Applied BioSciences, Faculty of Science and Engineering, Macquarie University, Sydney, Australia; 20Discipline
of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; 21Vector and Genome Engineering Facility, Children's
Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, Australia; 22Laboratory of Molecular Oncology and Innovative
Therapies, Military Institute of Medicine, Warszawa, Poland.
{These authors' contributed equally to this work.
An earlier draft of this article was posted as a preprint at bioRxiv (doi: content/10.1101/2022.09.28.510021v1).
The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors. Multiple clinical
trials have been undertaken for this target in the past 15 years; however, we are still to see market approval of the first
liver-targeted adeno-associated virus (AAV)-based gene therapy. Inefficient expression of the therapeutic transgene,
vector-induced liver toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses are
the main challenges to date. One of the contributing factors to the insufficient clinical outcomes, despite highly encouraging
preclinical data, is the lack of robust, biologically and clinically predictive preclinical models. To this end, this
study reports findings of a functional evaluation of 6 AAV vectors in 12 preclinical models of the human liver, with the
aim to uncover which combination of models is the most relevant for the identification of AAV capsid variant for safe
and efficient transgene delivery to primary human hepatocytes. The results, generated by studies in models ranging from
immortalized cells, iPSC-derived and primary hepatocytes, and primary human hepatic organoids to in vivo models,
increased our understanding of the strengths and weaknesses of each system. This should allow the development of novel
gene therapies targeting the human liver.
*Correspondence: Dr. Leszek Lisowski, Vector and Genome Engineering Facility, Children's Medical Research Institute, Faculty of Medicine and Health, The University of
Sydney, 214 Hawkesbury Road, Westmead, NSW 2145, Australia. E-mail: llisowski@cmri.org.au
HUMAN GENE THERAPY, VOLUME 34, NUMBERS 7 and 8
ª 2023 by Mary Ann Liebert, Inc.
DOI: 10.1089/hum.2022.188 j 273
Human Gene Therapy - April 2023

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