Adenoviral Vectors
Since the original idea of vector-based gene therapy, a great deal of progress in adenoviral vector development has been made. Judging from the published work using the adenoviral vectors, it is apparent that the existing adenoviral vectors have provided
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ADENOVIRAL VECTORS Prem Seth* Senior Scientist Human Gene Therapy Research Institute 1415 Woodland Avenue, Suite 218 Des Moines IA 50309
In recent years there has been a tremendous interest in the use of adenoviral vectors for the gene therapy of cancer. The main reasons for this are the ease with which recombinant adenoviruses can be constructed in the laboratory; can be grown to high titers; and can infect a variety of target cells including both and non-dividing cells. Another
advantage of using adenoviral vectors is the high level transient gene expression which appears to be sufficient for many cancer gene therapy purposes. The purpose of this chapter is to describe the biology of adenoviruses, the construction of the recombinant adenoviral vectors, and their important features. The problems associated with the use of adenoviral vectors and future considerations pertaining to vector development will be also be discussed. 1. ADENOVIRAL VECTORS-BIOLOGY Adenoviruses are DNA-containing, non-enveloped viruses. There are 49 human serotypes which are classified into six sub groups (groups A to F) (Shenk, 1996). Adenoviruses have natural tropism for the epithelial cells of upper and lower respiratory tracts, the gastro-intestinal tract and ocular tissue. The two most commonly used adenoviruses for constructing recombinant vectors are Ad2 and Ad5, mainly because of our greater understanding of their genomes and because these viruses have never been shown to induce tumors even in animal models. Adenoviral virions are icosahedral in shape, about 70 to l00nm diameter. The double stranded DNA and core proteins are surrounded by a protein shell composed of capsid proteins. The capsid contains 252 surface projections called capsomers, with 12 vertices. There are eleven structural proteins numbered from protein II to XII (Fig. 1) (Shenk, 1996). The three capsid proteins which participate actively in the entry of virus *Phone: 515-241-8727 (direct), 515-241-8787 (main office). Fax: 515-241-8788, e-mail: [email protected] Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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Figure 1. Adenovirus virion. A. The three-dimensional image reconstruction of the icosahedral capsid is viewed
along the threefold axis. The major coat protein hexon has a triangular top with three towers. Fibers protrude from the penton bases at each fivefold vertex, but only the first third of the shaft is imaged as the remainder
is washed out by the averaging method. Note that the capsid is rounded to provide a continuous protein shell. B. A stylized section summarizing current structural knowledge of the polypeptide components and the viral DNA. A real section through the icosahedral virion would not contain all these components (reprinted with permission from Field’s Virology 3rd edition).
in the cells are fiber (protein III), penton base (protein IV), and hexon (protein II). There are at-least 4 inner core proteins which are known to participate mainly in t
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