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

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 ef...

Full description

Saved in:
Bibliographic Details
Published in:Gene therapy 2016-01, Vol.23 (1), p.86-94
Main Authors: Simão, D, Pinto, C, Fernandes, P, Peddie, C J, Piersanti, S, Collinson, L M, Salinas, S, Saggio, I, Schiavo, G, Kremer, E J, Brito, C, Alves, P M
Format: Article
Language:English
Subjects:
Adenovirus
Adenoviruses
Adenoviruses, Canine - genetics
Adenoviruses, Human - genetics
Animals
Axonal Transport
Biochemistry, Molecular Biology
Care and treatment
Cell Differentiation
Cell Survival
Central Nervous System - metabolism
Cloning, Molecular
Dependoviruses
Disease Models, Animal
Gene expression
Gene Expression Regulation
Gene therapy
Gene Transfer Techniques
Genetic aspects
Genetic research
Genetic Therapy
Genetic Vectors
Health aspects
Human adenovirus
Human health and pathology
Humans
Life Sciences
Methods
Nervous system diseases
Neural Stem Cells - cytology
Neural Stem Cells - metabolism
Neurodegeneration
Neuroglia - metabolism
Neurons
Neurons - cytology
Neurons - metabolism
Testing
Transduction, Genetic
Transgenes
Vectors (Biology)
Viral Tropism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0969-7128
1476-5462
DOI:10.1038/gt.2015.75