Single amino acid insertion allows functional transduction of murine hepatocytes with human liver tropic AAV capsids

Marti Cabanes-Creus; Renina Gale Navarro; Sophia H.Y. Liao; Grober Baltazar; Matthieu Drouyer; Erhua Zhu; Suzanne Scott; Clement Luong; Laurence O.W. Wilson; Ian E. Alexander; Leszek Lisowski

Molecular Therapy: Methods & Clinical Development (Jun 2021)

Single amino acid insertion allows functional transduction of murine hepatocytes with human liver tropic AAV capsids

Marti Cabanes-Creus,
Renina Gale Navarro,
Sophia H.Y. Liao,
Grober Baltazar,
Matthieu Drouyer,
Erhua Zhu,
Suzanne Scott,
Clement Luong,
Laurence O.W. Wilson,
Ian E. Alexander,
Leszek Lisowski

Affiliations

Marti Cabanes-Creus: Translational Vectorology Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
Renina Gale Navarro: Translational Vectorology Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
Sophia H.Y. Liao: Translational Vectorology Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
Grober Baltazar: Translational Vectorology Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
Matthieu Drouyer: Translational Vectorology Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
Erhua Zhu: Gene Therapy Research Unit, Children’s Medical Research Institute and The Children’s Hospital at Westmead, The University of Sydney, Westmead, NSW 2145, Australia
Suzanne Scott: Gene Therapy Research Unit, Children’s Medical Research Institute and The Children’s Hospital at Westmead, The University of Sydney, Westmead, NSW 2145, Australia; Australian e-Health Research Centre, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Sydney, NSW 2113, Australia
Clement Luong: Translational Vectorology Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
Laurence O.W. Wilson: Australian e-Health Research Centre, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Sydney, NSW 2113, Australia
Ian E. Alexander: Gene Therapy Research Unit, Children’s Medical Research Institute and The Children’s Hospital at Westmead, The University of Sydney, Westmead, NSW 2145, Australia; Discipline of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia
Leszek Lisowski: Translational Vectorology Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia; Vector and Genome Engineering Facility, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia; Military Institute of Medicine, Laboratory of Molecular Oncology and Innovative Therapies, 04-141 Warsaw, Poland; Corresponding author: Leszek Lisowski, Translational Vectorology Research Unit, Children’s Medical Research Institute, The University of Sydney, 214 Hawkesbury Road, Westmead, NSW 2145, Australia.

Journal volume & issue: Vol. 21
pp. 607 – 620

Abstract

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Recent successes in clinical gene therapy applications have intensified the interest in using adeno-associated viruses (AAVs) as vectors for gene delivery into human liver. An inherent intriguing characteristic of AAVs is that vector variants vary substantially in their ability to transduce hepatocytes from different species. This has historically limited the value of preclinical studies using rodent models for predicting the efficiency of AAV vectors in liver-targeted gene therapy clinical studies. In this work, we aimed to investigate the key determinants of the observed differential interspecies transduction abilities among AAV variants. We took advantage of domain swapping strategies between AAV-KP1, a newly identified variant with enhanced murine liver tropism, and AAV3b, which functions poorly in mice. The systematic in vivo comparison of AAV3b/AAV-KP1 chimeric variants allowed us to identify a threonine insertion at position 265 within variable region I (VR-I) as the key residue that confers murine hepatic transduction to human-derived clade B (AAV2-like) and clade C (AAV3b-like) variants. We propose to use this insertion to generate phylogenetically related AAV surrogates in support of toxicology and dosing studies in the murine liver model.

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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