ABSTRACT

I. INTRODUCTION A. Why Drug-Regulated Gene Transfer? The Orkin-Motulsky report, a critical review of gene therapy published in December 1995 [1], highlighted the need for “improving vectors for gene delivery, enhancing and maintaining high-level expression of genes transferred to somatic cells, achieving tissue-specific and regulated expression of transferred genes, and directing gene transfer to specific cell types.” Gene transfer was deemed to be very early in development. Since the report was published, gene transfer methods have made significant improvements, particularly for helper-dependent adenoviral vectors delivered intravenously [2-4] (see Chap. 7), for adenovirus-associated virus (AAV) vectors delivered intravenously or intramuscularly [5-7] (see Chap. 8), and for plasmids delivered intramuscularly with the assistance of in vivo electroporation [8-10] (Chap. 10). These systems have demonstrated the ability to maintain the production of secreted proteins at therapeutic levels for months to years in rodents and larger animals.