6 Strategies to Adapt Adenoviral Vectors for Gene Therapy Applications: Targeting and Integration

Abstract

For the effective application of gene therapy strategies to human disease, Anderson suggested that certain criteria should be met; namely, that vectors should deliver a therapeutic gene specifically to a target cell, that resultant gene expression should be at an appropriate level and for an appropriate period of time, and that delivery and expression of the therapeutic gene should be achieved within an acceptable safety margin (Anderson and Fletcher 1980). These criteria remain largely unmet. However, in recent years, disappointment in the results of clinical trials has forced a refocusing on the basics of vector design, resulting in steady advancements in vector technology that now show promise for more successful gene therapy.

Development of vectors that have in vivo efficacy is critical because many diseases for which gene therapy can be rationally considered require direct in situ gene delivery and cannot feasibly be addressed by an ex vivo approach. Replication-incompetent adenovirus is a potential candidate vector for clinical gene therapy based on several key attributes that include ease of production to high titer, infection of both dividing and nondividing cells, and systemic stability, which has allowed for efficient in vivo gene expression (Brody and Crystal 1994). However, the virus has several important limitations including its widespread tropism, stimulation of inflammatory and immune responses, and short-term transgene expression (Yang et al. 1995Yang et al. 1996; Tomko et al. 1997). This chapter focuses chiefly on the issue of targeted gene delivery to address the limitations brought about by native viral tropism. To date, several...