Advances in the development of herpes simplex virus-based gene transfer vectors for the nervous system

Herpes simplex virus (HSV) is an attractive candidate vector for treatment of nervous system disease by gene therapy. Here we review molecular aspects of the natural biology of HSV as it relates to vector design and application. Although gene transfer and transient expression was readily achieved using first generation replication defective HSV vectors, these vectors did not provide for long-term transgene expression, a prerequisite for effective treatment of neurodegenerative disease. The principle impediments to effective use of HSV vectors are residual toxicity of non-replicating vectors and the silencing of transgene expression from persisting latent viral genomes in neurons. Recent advances suggest that vectors deleted for multiple immediate early viral genes provide a solution to both of these problems and thereby provide for the first time insight into methods for the effective design of useful gene vectors for central nervous system applications.