Scientific publications

Assessment of Pre-Clinical Liver Models Based on Their Ability to Predict the Liver-Tropism of Adeno-Associated Virus Vectors

Apr 17, 2023 | Magazine: Human Gene Therapy

Adrian Westhaus 1 2, Marti Cabanes-Creus 1, Kimberley L Dilworth 1, Erhua Zhu 3, David Salas Gómez 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 10 11, Bang Manh Tran 12, Elizabeth Vincan 12 13 14, Sharon L Wong 15 16, Shafagh A Waters 15 16 17, Georgina E Riddiough 12 18, Marcos V Perini 18, Laurence O W Wilson 5 19, Julien Baruteau 9 10 11, Sebastian Diecke 8, Gloria González-Aseguinolaza 4, Giorgia Santilli 2, Adrian J Thrasher 2, Ian E Alexander 3 20, Leszek Lisowski 1 21 22


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.

CITA DEL ARTÍCULO Hum Gene Ther. 2023 Apr;34(7-8):273-288. doi: 10.1089/hum.2022.188.