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Assessment of pre-clinical liver models based on their ability to predict the liver-tropism of adeno-associated virus vectors

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Item Type:Article
Title:Assessment of pre-clinical liver models based on their ability to predict the liver-tropism of adeno-associated virus vectors
Creators Name:Westhaus, A. and Cabanes Creus, M. and Dilworth, K.L. and Zhu, E. and Salas, D. and Navarro, R.G. and Amaya, A.K. and Scott, A. and Kwiatek, M. and McCorkindale, A.L. and Hayman, T.E. and Frahm, A. and Perocheau, D. and Tran, B.M. and Vincan, E. and Wong, S.L. and Waters, S.A. and Riddiough, G.E. and Perini, M.V. and Wilson, L.O.W. and Baruteau, J. and Diecke, S. and Gonzalez-Aseguinolaza, G. and Santilli, G. and Thrasher, A.J. and Alexander, I.E. and Lisowski, L.
Abstract:The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors (rAAV). 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 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 six AAV vectors in twelve 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.
Keywords:Capsid Proteins, Dependovirus, Genetic Therapy, Genetic Vectors, Hepatocytes, Liver, Tropism
Source:Human Gene Therapy
Publisher:Mary Ann Liebert
Page Range:273-288
Date:April 2023
Official Publication:https://doi.org/10.1089/hum.2022.188
PubMed:View item in PubMed

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