Adenoviruses as Gene Delivery Vectors
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ADENOVIRUSES AS GENE DELIVERY VECTORS Anu-Maaria Sandmair1,2*, Matti Vapalahti2,4, and Seppo Ylä-Herttuala1,3,4 1
A.I.Virtanen Institute University of Kuopio P.O.B. 1627, FIN-70211 Kuopio Finland 2 Department of Neurosurgery 3 Department of Medicine and 4 Gene Therapy Unit University Hospital of Kuopio P.O.B. 1777, FIN-70110 Kuopio Finland
1. DEFINITION Adenoviral gene transfer vector is a genetically modified adenovirus in which a portion of the normal viral genome has been deleted to prevent viral replication and replaced with a new gene or genes to be delivered into target cells (Culver, Rigolet and Raffel, 1997).
2. HISTORY Adenoviruses were first cultured and reported as distinct viral agents in 1953 (Rowe et al., 1953). Similar viral agents were isolated from febrile military personnel with a variety of respiratory illnesses and it was soon realized that there were multiple serotypes of adenoviruses. Acute respiratory disease syndromes caused by adenoviruses had been defined for 100 years before their association with this group of viruses (Horwitz, 1990). Adenovirus serotypes used for gene transfer are not associated with human malignancies. Graham et al. constructed an adenovirus complementing 293 cell line, which was the basis for adenovirus—mediated gene therapy (Graham et al., 1977). Furthermore, Spector et al. showed that in 293 cell line the replication of E1 deleted viruses was possible via complementation of integrated sequencies (Spector et al., 1980). * Fax:+358-17-163030 Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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3. WILD TYPE ADENOVIRUSES Adenovirus infections occure worldwide in humans as well as in a variety of animals. With a few exceptions, human adenovirus serotypes are generally not pathogenic to animals and animal adenoviruses are only pathogenic within their own species. Approximately 5% of the acute respiratory disease in children under the age of 5 is due to adenoviruses (Horwitz, 1990). Antibodies to serotypes 1, 2 and 5 are most common and are present in 40% to 60% of children (Horwitz, 1990). More than 10 million people have been immunized safely with serotypes 4 and 7 (Horwitz, 1990). The usual symptoms include nasal congestion, cough, fever, myalgia and headache. Some serotypes can cause conjunctivitis, pneumonia, gastroenteritis, acute hemorrhagic cystitis and rarely meningoencephalitis. Specific antiviral therapy for adenovirus infections have been attempted but were unsuccessful. Effective oral vaccines exist to prevent disease by some adenoviruses and have been used for over 20 years in military recruits (Brody et al., 1994).
4. ADENOVIRUS AS A GENE THERAPY TOOL Adenoviruses have been used in modern molecular biology for in vivo delivery of cloned DNA for therapy of cancer and various other diseases. Adenoviruses can be designed to enter cells and express genes of interest. However, they are made replicationdeficient in order to prevent production of infec
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