Transduction of brain by herpes simplex virus vectors

An imposing obstacle to gene therapy is the inability to transduce all of the necessary cells in a target organ. This certainly applies to gene transfer to the brain, especially when one considers the challenges involved in scaling up transduction from animal models to use in the clinic. Non-neurotropic viral gene transfer vectors (e.g., adenovirus, adeno-associated virus, and lentivirus) do not spread very far in the nervous system, and consequently these vectors transduce brain regions mostly near the injection site in adult animals. This indicates that numerous, well-spaced injections would be required to achieve widespread transduction in a large brain with these vectors. In contrast, herpes simplex virus type 1 (HSV-1) is a promising vector for widespread gene transfer to the brain owing to the innate ability of the virus to spread through the nervous system and form latent infections in neurons that last for the lifetime of the infected individual. In this review, we summarize the published literature of the transduction patterns produced by attenuated HSV-1 vectors in small animals as a function of the injection site, and discuss the implications of the distribution for widespread gene transfer to the large animal brain.