2.1. History of gene therapy research

The term “genetic engineering” was first used at the Sixth International Congress of Genetics held in Ithaca, New York, in 1932, and it was taken to mean “the application of genetic principles to animal and plant breeding.” The term “gene therapy” was later coined to distinguish it from the ominous, germ-line implications of the term “human genetic engineering.” Gene therapy means the treatment of human disease by transfer of therapeutic genetic material into specific somatic cells of a patient instead of using ­conventional drugs (Wolff & Lederberg 1994, Mulligan 1993). In this process, DNA would be considered the ultimate drug.

The most fundamental milestones in gene therapy development were the elucidation of the structure of DNA by Watson & Crick 1953, Kornberg`s first successful replication of DNA in a test tube and the first demonstrations of cellular uptake of naked genomic DNA in cell culture in 1962 (Wolff & Lederberg 1994). Once the basis of molecular genetics and gene transfer in bacteria had been established in the 1960s, gene transfer into animals and humans using either viral vectors and/or genetically modified cultured cells became possible. In the late 1970s, these early transfection techniques were combined with selection systems for cultured cells and recombinant DNA technology (Graham & Van Der Eb 1973). With the development of retroviral vectors in the 1980s, gene transfer into mammalian cells for the purpose of gene therapy became possible (Dubensky et al. 1984, ­Wilson et al. 1988). The introduction of new and powerful strategies to identify and sequence the estimated 80 000 genes comprising the human genome has created one of the basic conditions for further development of gene therapy (Crystal 1995a).

Human gene transfer was pioneered by Blaese & Anderson 1990, who were the first to introduce successfully the adenosine deaminase (ADA) gene into T-lymphocytes of an ADA-deficient patient (Blaese & Anderson 1990). This was the first federally approved human gene therapy protocol for the correction of an ADA deficiency, and it was begun in September 1990 (Anderson 1992). ADA-deficient patients suffer from severe immunodeficiency and subsequent infections because of a mutation in the adenosine deaminase gene. Rosenberg et al. in 1993 were the first to use retroviral vectors in a human cancer gene therapy trial (Rosenberg et al. 1993, Wivel & Walters 1993). To date, human gene therapy has been clinically used in over 300 trials involving more than 2000 patients (Morgan & Anderson 1993, Oldfield et al. 1993, Crystal et al. 1995b, Sobol & Scanlon 1995, Tursz et al. 1996, Zabner et al. 1996, Imai & Isaka 1998, Laitinen et al. 1998, Human gene marker/therapy clinical protocols 1999). To be exact, total of 313 human gene therapy protocols were registered in the USA and 36 international protocols by the end of 1999. Potentially, the present technology of gene transfer may provide correction of cellular function by expressing the deficient gene, or it may add a new function to a cell by transferring an exogenous gene or inhibit the unfavorable action of a cell by introducing a counteracting gene (Imai et al. 1998).