Evaluation of helper-dependent canine adenovirus vectors in a 3D human CNS model

Daniel Simão, C. Pinto, P. Fernandes, Christopher J. Peddie, Stefania Piersanti, Lucy M Collinson, Sara Salinas, Isabella Saggio, Giampietro Schiavo, Eric J. Kremer, C. Brito, P. M. Alves

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Gene therapy is a promising approach with enormous potential for treatment of neurodegenerative disorders. Viral vectors derived from canine adenovirus type 2 (CAV-2) present attractive features for gene delivery strategies in the human brain, by preferentially transducing neurons, are capable of efficient axonal transport to afferent brain structures, have a 30-kb cloning capacity and have low innate and induced immunogenicity in preclinical tests. For clinical translation, in-depth preclinical evaluation of efficacy and safety in a human setting is primordial. Stem cell-derived human neural cells have a great potential as complementary tools by bridging the gap between animal models, which often diverge considerably from human phenotype, and clinical trials. Herein, we explore helper-dependent CAV-2 (hd-CAV-2) efficacy and safety for gene delivery in a human stem cell-derived 3D neural in vitro model. Assessment of hd-CAV-2 vector efficacy was performed at different multiplicities of infection, by evaluating transgene expression and impact on cell viability, ultrastructural cellular organization and neuronal gene expression. Under optimized conditions, hd-CAV-2 transduction led to stable long-term transgene expression with minimal toxicity. hd-CAV-2 preferentially transduced neurons, whereas human adenovirus type 5 (HAdV5) showed increased tropism toward glial cells. This work demonstrates, in a physiologically relevant 3D model, that hd-CAV-2 vectors are efficient tools for gene delivery to human neurons, with stable long-term transgene expression and minimal cytotoxicity.

Original languageEnglish
Pages (from-to)86-94
Number of pages9
JournalGene Therapy
Volume23
Issue number1
DOIs
Publication statusPublished - 1 Jan 2016

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    Simão, D., Pinto, C., Fernandes, P., Peddie, C. J., Piersanti, S., Collinson, L. M., ... Alves, P. M. (2016). Evaluation of helper-dependent canine adenovirus vectors in a 3D human CNS model. Gene Therapy, 23(1), 86-94. https://doi.org/10.1038/gt.2015.75