Replication-defective genomic HSV gene therapy vectors: design, production and CNS applications

Herpes simplex virus (HSV) is a neurotropic double-stranded DNA virus. In an unmodified form it is a human pathogen, causing recurrent cold sores, keratitis and, rarely, severe encephalitis. Elimination of pathogenic functions results in the generation of a valuable gene transfer vector for neurological applications. Replication-defective genomic HSV-based vectors are highly infectious, and efficiently transduce and express transgenes in a broad range of both dividing and non-dividing cells. Clinically relevant yields of clinical grade vector can be produced by growth in cell lines that complement the viral functions that are deleted in the vectors to eliminate pathogenicity. The viral genome is over 150 kb in length and many of the viral genes may be deleted without compromising viral growth in vitro, and therefore large or multiple transgenes can be accommodated within the vectors. The wild-type virus adopts a lifelong latent state in neurons of sensory ganglia. This property can be exploited in the generation of vectors to allow long-term transgene expression in neurons. In this review, we summarize recent progress in the areas of vector development and vector production, and in developing gene transfer therapeutics to treat malignant glioma.