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Gene Ther. 2016 Jan;23(1):86-94. doi: 10.1038/gt.2015.75. Epub 2015 Aug 20.

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

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iBET-Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.
Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.
The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London, UK.
Dipartimento di Biologia e Biotecnologie 'Charles Darwin', Università di Roma La Sapienza, Rome, Italy.
Institut de Génétique Moléculaire de Montpellier, Montpellier, France.
Université Montpellier, Montpellier, France.
Istituto Pasteur Fondazione Cenci Bolognetti, Università di Roma La Sapienza, Rome, Italy.
Istituto di Biologia e Patologia Molecolari del CNR, Università di Roma La Sapienza, Rome, Italy.
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK.


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.

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