In Search of Adeno-Associated Virus Vectors With Enhanced Cardiac Tropism for Gene Therapy

Natsuki Sasaki; Cindy Y Kok; Adrian Westhaus; Ian E Alexander; Leszek Lisowski; Eddy Kizana

doi:10.1016/j.hlc.2023.06.704

In Search of Adeno-Associated Virus Vectors With Enhanced Cardiac Tropism for Gene Therapy

Heart Lung Circ. 2023 Jul;32(7):816-824. doi: 10.1016/j.hlc.2023.06.704. Epub 2023 Jul 12.

Authors

Natsuki Sasaki¹, Cindy Y Kok², Adrian Westhaus³, Ian E Alexander⁴, Leszek Lisowski⁵, Eddy Kizana⁶

Affiliations

¹ The Centre for Heart Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
² The Centre for Heart Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia; Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
³ Translational Vectorology Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁴ Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁵ Translational Vectorology Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland.
⁶ The Centre for Heart Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia; Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Cardiology, Westmead Hospital, Sydney, NSW, Australia. Electronic address: eddy.kizana@sydney.edu.au.

PMID: 37451880
DOI: 10.1016/j.hlc.2023.06.704

Abstract

Globally, adeno-associated virus (AAV) vectors have been increasingly used for clinical gene therapy trials. In Australia, AAV-based gene therapy is available for hereditary diseases such as retinal dystrophy or spinal muscular atrophy 1 (SMA1). Many preclinical studies have used AAV vectors for gene therapy in models of cardiac disease with outcomes of varying translational potential. However, major barriers to effective and safe therapeutic gene delivery to the human heart remain to be overcome. These include tropism, efficient gene transfer, mitigating off-target gene delivery and avoidance of the host immune response. Developing such an enhanced AAV vector for cardiac gene therapy is of great interest to the field of advanced cardiac therapeutics. In this review, we provide an overview of the approaches currently being employed in the search for cardiac cell-specific AAV capsids, ranging from natural AAVs selected as a result of infection and latency in the heart, to the use of cutting-edge molecular techniques to engineer and select AAVs specific for cardiac cells with the use of high-throughput methods.

Keywords: Adeno-associated virus; Barcode-seq; Cardiac gene therapy; Directed evolution; Natural occurring AAV.

Publication types

Review

MeSH terms

Dependovirus* / physiology
Gene Transfer Techniques*
Genetic Vectors
Humans
Viral Tropism*