Virus vectors for gene delivery to the nervous system

Abstract

A number of virus vectors have been developed for gene delivery to the nervous system. Virus vectors still provide the most efficient means of gene delivery, and this is critical as only a small volume of inoculum can be used without damaging neurons. Each of the four types of vectors currently in use have their advantages and disadvantages. Highest titers can be achieved with herpes virus and adenovirus vectors, with retrovirus and adeno-associated virus (AAV) vectors currently yielding lower titers. The transgene capacity of each from highest to lowest is: herpes virus (30 kb), adenovirus (8-10 kb), retrovirus (7-8 kb) and AAV (4.5 kb). All can infect a broad range of cell types in the nervous system, including neurons, glia and endothelial cells. Herpes, adenovirus and AAV vectors can deliver genes to postmitotic, as well as mitotic cells, while retrovirus vectors depend on cell mitosis for gene delivery. Herpes virus can assume a stable extrachromosomal configuration in the nuclei of some neurons (termed latency), while both retrovirus and AAV can integrate into the cell genome. Both integrate at random sites, but AAV can also integrate at a specific chromosomal location. Adenovirus neither assumes a stable state nor integrates, still its genome can persist and be expressed in the host cell for some time (up to a month or so). Stability of gene expression is a problem for all the vectors, due in part to the use of viral promoters which tend to be down-regulated by the host cell over a month or so. Both herpes virus vectors and adenovirus vectors have some toxicity in their current configurations, while retrovirus and AAV tend to be associated with less neuropathogenicity. Many developments in vectors should be occurring over the next few years that should increase the potential of these vectors for therapeutic gene delivery.