Development and application of herpes simplex virus vectors for human gene therapy

Advances in understanding the molecular basis of human disease and the development of recombinant DNA methods is rapidly creating new means of disease diagnosis and treatment. Among the most revolutionary developments are technologies for transfer of therapeutic genes to the human body to treat both inherited and acquired disease. Gene therapy offers considerable promise for ameliorating otherwise intractable diseases such as immunopathological conditions, cancer, heart disease, and various metabolic and neurodegenerative syndromes. To fulfill this promise, more efficient and effective methods of gene delivery and appropriate gene expression must be developed. The lack of such techniques is currently the most significant impediment to the use of genetic therapy. Both viral and nonviral delivery systems are under development for specific gene-therapy applications. Herpes simplex virus (HSV) represents a novel vector system for gene delivery to the nervous system and other tissues. HSV is able to establish latency in nondividing neuronal cells in which genomes persist long-term but do not integrate or alter host-cell metabolism and that carry a promoter system uniquely capable of escaping repression that shuts off the expression of HSV-lytic genes during latency. This review examines efforts to create defective HSV vectors that are safe, noncytotoxic, and applicable to the treatment of cancer and diseases affecting peripheral nerves. Perhaps the most important use of HSV vectors will be for the treatment of neurodegenerative diseases of the brain, but additional studies are required to improve the design of promoters to ensure regulatable or effective levels of therapeutic gene expression.