Introduction A General Overview

Research into the genetic foundations of disease, both acquired and inherited, has fostered progress of molecular medicines. Exemplified by the recent decoding of the complete human and mouse genomes; medical scientists have ever-expanding tools useful to engineer and employ therapeutic gene transfer in medical research programs. In contrast to traditional drugs, which act by modifying existing gene product activity, therapeutic gene transfer, or gene therapy, alters the genetic makeup of the cell with the intention of ameliorating the target disease phenotype. Successful gene therapy requires the identification of therapeutic genes that will correct a genetic defect or rectify a disease process, as well as the design and construction of suitable vehicles for delivery and expression of these genes in vivo. Identification of genes with therapeutic potential and engineering of effective gene transfer vectors are rapidly proceeding, making gene therapy an imminent practical reality. Considerable progress has been made in vector design, and clinical trials for the treatment of a number of diseases are underway. Success in these initial gene therapy endeavors is providing incentive for research into additional gene therapy applications, holding promise for creating a new age of molecular medicine in which genomics and proteomics dovetail with genetic diagnostics and therapeutic gene transfer.

Although remarkable progress has been made in the development of gene vector technologies, substantial hurdles remain. These include the development of strategies for vector targeting, modifications to increase transgene stability, regulation of gene expression, and circumvention of undesirable immune responses. Delivery of transgenes into target cells can be accomplished using either viral or nonviral vectors, with viral strategies remaining the most prevalent in human clinical trials. Virus-mediated gene delivery requires efficient methods for vector construction, vector production, and target cell infection. In this chapter, the relative merits and potential applications of herpes simplex virus type 1 (HSV-1) vectors are discussed. In the context of vector development, the natural history of HSV infection in the host is reviewed, highlighting unique features of the virus biology. Remaining potential pitfalls and approaches to their solution are also discussed.

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