The great potential of gene therapy has recently been supported by successful treatments of immune deficiency and cancer patients (1,2). However, much remains to be solved before gene therapy becomes a standard procedure. One major obstacle is the low efficiency of gene transfer (3); thus, further development of vectors is necessary. In this context, baculovi-ruses have raised increasing interest because they have a long history as safe and efficient gene delivery tools in insect cells (4), and the long-lived dogma of incompability with mammalian cells has recently been revised (5-7).

Baculoviruses are common in nature and the food that we consume, and have been known for hundreds of years. Still, no diseases have been linked to baculoviruses in any organism outside the phylum Arthropoda (8). Baculoviruses have been studied extensively since the 1950s as biopesticides (9) and, therefore, a lot of data are available about their biology (8) and biosafety (10). The baculovirus expression vector system (BEVS) became a popular choice for recombinant protein production during the late 1980s and 1990s, with a large number of commercially available reagents (4).

It became evident already in early 1980s that baculoviruses can penetrate into nontarget cells, including many human cell lines, but non productively. No viral replication or gene expression could be detected (11,12). However, in 1985, Car-bonell et al. (13) reported a successful transduction of mammalian cells by a recombinant baculovirus bearing a promoter active in target cells [Rous sarcoma virus (RSV) long terminal repeat promoter] as part of the recombinant baculovirus genome. In 1995, Hofmann et al. (14) confirmed these results. They were also the first to suggest baculovirus-mediated gene therapy. There was a 10-year gap between these 2 papers probably because Carbonell et al. (15,16) later claimed that their initial findings of low-level gene expression in mammalian cells were due to pseudotransduction. During the late 1990s the concept of baculovirus-mediated gene transfer was further verified and the list of suitable target cells is still continuously increasing.

The fact that baculoviruses are efficiently destroyed by complement (17) delayed the first successful in vivo applications of baculovirus-mediated gene transfer to the beginning of the new millennium (5), although the feasibility of these viruses in an ex vivo perfusion model was reported soon after baculoviruses were suggested as tools for gene therapy (17). Several recent reports have also highlighted the use of bacu-loviruses in in vivo applications, especially in immune-privileged tissues such as brain or eye (18-20). Indeed, baculoviruses offer many advantages compared with other viral vectors in terms of safety, high capacity for the incorporation of foreign DNA, and easy production (Table 1). This chapter provides a detailed overview of the history as well as current status of baculovirus-mediated gene delivery. Future trends in baculovirus-mediated gene therapy are also discussed. For more detailed background on baculoviruses, the reader can refer to an excellent book, ''The Baculoviruses,'' edited by Miller (8) and a laboratory manual by O'Reilly et al. (4) de-

Table 1 Properties of Recombinant Baculoviruses that Make Them Suitable for Gene Therapy



Easy to manipulate and produce


at high titers (> 1010 pfu/mL)

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