ReviewSuicide genes: past, present and future perspectives
Section snippets
Evolving methods of gene delivery
Several techniques have been developed for transferring genes across the cell membrane (Table 1), many of which are applicable to suicide gene therapy (reviewed in 6, 7). These can be categorized as: (1) physical methods for disrupting the target cell membrane by mechanical or electrical means; (2) chemical methods that employ a variety of non-liposome and liposome-based facilitators; (3) recombinant viral vectors developed from early systems that are based on manipulation of the papilloma
Optimizing gene delivery
A major problem in gene delivery is that the methods described above have characteristics, each of which can present as either an obstacle, or an aid, to gene transfer. This idiosyncrasy depends on the size of the DNA construct, whether transient or sustained expression of the gene is required, the anatomical site(s) of the lesion, target tissue type, whether the transfer is to be carried out in vitro, in vivo or ex vivo, and vector type (Table 2). Thus, hybridization of these techniques has
Development of suicide gene therapy
Originally, the suicide gene was conceptualized to act first, as a failsafe mechanism in retroviral vectors and second, as a phenotypic marker for scoring transfection rates. The promiscuous ability of retroviruses to infect a variety of cell types made them popular vectors for gene transfer. However, the random nature of their integration into host chromosomes has led to fears that the promoter element might cause downstream activation of an oncogene or a gene that encodes for some growth
Pre-clinical studies in mouse and rat models
The formulation of a hypothesis from the initial flash of inspiration requires validation in the laboratory before any clinical application. The use of animal models that phenotypically mirror manifestations of the human disease in question is essential. Scientific literature is replete with mouse and rat models of human disorders and, if inherent physiological differences are borne in mind, provide a convenient and relatively cheap vehicle for pre-clinical studies (Table 3). Information that
Human studies and clinical trials
Ethical approval was given for the first gene therapy clinical trial as recently as 1990 and over 300 more such trials have been initiated. Although a majority of these trials are in Phase I/II stage, it is indicative of the rate at which this field is progressing and the urgency for this therapy. Over half of these trials involve therapeutic approaches to malignant disorders with approximately 40 for the correction of monogenic diseases such as severe combined immunodeficiency–adenosine
Concluding remarks
The need for gene therapy is paramount and the role of suicide genes as primary therapeutic agents and as safety switches in the delivery of other genes has been established. Although encouraging results are emerging from pre-clinical and clinical studies, the need for more efficient and specific methods of delivery are constantly being highlighted. Promising new avenues of research point to the eventual dovetailing of suicide gene therapy with more traditional therapies, resulting in novel
Acknowledgements
We thank J. Wessels for help in preparing the diagrams and M. Eyrich for comments and suggestions. S.L. is the recipient of a Graduate Student Fellowship from the fortüne Foundation of the University Clinic of Tübingen. We acknowledge support from the fortüne Program (grants #375/1996 and #438/1997), the Deutsche Forschungsgemeinschaft (grants SFB510-C4 and La649/11-1), the Federal Ministry of Education, Science, Research and Technology (grant Fö. 01KS9602), the Interdisciplinary Research
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