Development of optimized vectors for gene therapy

The promise of gene therapy and its potential to generate effective treatments for human diseases has been a subject of much debate. It is now well recognized that gene delivery technology presents the major obstacle to the success of this field, and a consensus has emerged that the development of vectors that can deliver and appropriately express relevant gene products in specific tissues in vivo is much needed. For this reason, significant effort has been placed on expanded studies in molecular virology and gene expression relevant to gene-transfer technology (reviewed in ref. 1). The challenge has been to achieve stable, regulated gene expression and to avoid immune responses. Thus, the ideal gene therapy vector would be injectable, targetable to specific sites in vivo, regulatable, able to maintain long-term gene expression, and nonimmunogenic. In this issue of the Proceedings, Burcin and colleagues (2) in Dr. Bert O’Malley’s laboratory describe a major step toward the generation of an optimized adenoviral vector. This vector could be useful for the treatment of liver-related diseases and serum-protein deficiencies that can be complemented through gene expression in hepatocytes. In this study, several elements have been combined into a single vector with promising features (Fig. 1). Although the individual components are not by themselves entirely novel, the fact that they work in combination represents a pragmatic advance in the development of an optimal adenoviral vector. Importantly, Burcin et al. used an adenoviral vector gutted of almost the entire adenoviral genome, replaced with a sequence from the human HPRT gene. Such vectors have been shown to …