VIRUS VECTORS FOR GENE DELIVERY TO THE NERVOUS-SYSTEM

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 inocu lum can be used without damaging neurons. Each of the four types of ve ctors currently in use have their advantages and disadvantages. Highes t liters can be achieved with herpes virus and adenovirus vectors, wit h retrovirus and adeno-associated virus (AAV) vectors currently yieldi ng lower liters. The transgene capacity of each from highest to lowest is: herpes virus (30 kb), adenovirus (8-10 kb), retrovirus (7-8 kb) a nd AAV (4.5 kb), All can infect a broad range of cell types in the ner vous system, including neurons, glia and endothelial cells. Herpes, ad enovirus and AAV vectors can deliver genes to postmitotic, as well as mitotic cells, while retrovirus vectors depend on cell mitosis for gen e delivery. Herpes virus can assume a stable extrachromosomal configur ation in the nuclei of some neurons (termed latency), while both retro virus and AAV can integrate into the cell genome. Both integrate at ra ndom sites, but AAV can also integrate at a specific chromosomal locat ion. Adenovirus neither assumes a stable state nor integrates, still i ts 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 a ll the vectors, due in part to the use of viral promoters which tend t o be down-regulated by the host cell over a month or so. Both herpes v irus vectors and adenovirus vectors have some toxicity in their curren t configurations, while retrovirus and AAV tend to be associated with less neuropathogenicity. Many developments in vectors should be occurr ing over the next few years that should increase the potential of thes e vectors for therapeutic gene delivery.