Neurotropism and Retrograde Axonal Transport of a Canine Adenoviral Vector: A Tool for Targeting Key Structures Undergoing Neurodegenerative Processes

Viral tropism refers to the ability of a virus to selectively infect a given subset of cells. It relies on a variety of viral and host determinants that entail virus binding and entry into target cells, in addition to the presence of genetic elements that allow or enhance viral gene expression in a specific manner. Here we report the results of neuroanatomical studies in rat brains injected in different cerebral structures with vectors derived from the canine adenovirus type 2 (CAV2), whose natural target is the respiratory epithelium. Control animals injected with vectors derived from the human adenovirus type 5 (Ad5) displayed the previously documented pattern of gene transfer into both neurons and glial cells. Injection of CAV2 vectors resulted in selective transduction of neuronal cells. Cy3-labeled CAV2 particles allowed us to establish the high affinity of this vector for neuronal processes in vitro and their rapid uptake and retrograde axonal transport in vivo. After intrahippocampal injections, labeled particles were found, within 1 hour, closely associated to the nuclei of the neurons in layer II of the entorhinal cortex. Injections into the striatum resulted in a massive transduction of dopaminergic neurons in the substantia nigra compacta. The high efficiency with which CAV2 vectors are retrogradely transported opens the possibility of targeting a transgene to neuron populations remote from the injection site and difficult to access. Our data support the possibility to target key structures undergoing a degenerative process: the enthorhinal cortex, which is affected first in Alzheimer's disease; and the substantia nigra compacta, which undergoes degeneration in Parkinson's disease.