Chapter 1. Introduction

Gene therapy is a novel, rapidly developing form of therapy for both genetic and acquired diseases (Miller 1992, Crystal 1995b). In this strategy, nucleic acid, usually in the form of DNA, is administered into somatic cells to correct or replace a genetic defect or to modify the genetic properties of cells by, for example, producing therapeutic or immunostimulatory proteins. Progress in recombinant DNA technology has enabled the construction of genes to be transferred, and the development of vehicles, called vectors, for the transportation of these transgenes into the target cells has resulted in extensive research aiming at human gene therapy. Human gene therapy research is a strictly regulated scientific and technological progress, and so far, genetic modification of human germ-line cells is prohibited by the governments in both Europe and the USA (Wivel & Walters 1993, Bayertz 1994, Council of Europe 1997, Suomen sosiaali- ja terveysministeriö 1999).

The possible gene therapy applications are numerous. Inherited single-gene disorders, such as cystic fibrosis (CF), α1-antirypsin deficiency and Alport syndrome, are logical candidates for correction of the genetic defect by transferring a normal copy of the defective gene into the affected cells. In practice, however, this has proved more complicated than it was initially assumed. So far, most of the ongoing human clinical trials deal with gene therapies of acquired diseases, mostly cancer.

The new field of gene therapy combines the advantages of pharmacology and surgery: it enables treatment of diseases by externally administered substances with specific activities and an ability to alter tissues or organs permanently. The cornerstones of human gene therapy research are the development of safe and effective vectors for gene transfer and the development of non-surgical and surgical methods for delivering the vectors into the target cells and tissues. Finally, the need for appropriate control of transgene expression in the target cell is the third central issue in this research. So far, the most extensively used vectors – retrovirus, adenovirus, liposomes – have not proved optimal because of the inefficient transduction, immunogenicity and possible insertional mutagenesis related to the use of retroviruses (Crystal 1995b). Various methods have been used for vector delivery into target cells in vivo in animal studies and human clinical trials (Oldfield et al. 1993, Sobol & Scanlon 1995). None of them have proved especially effective in the treatment of human disease. Ex vivo gene transfer into harvested cells and implantation of these cells into an individual seems to be a multi-step, complicated and ineffective process, which is unsuitable to gene delivery into, for example, the lungs and kidneys (Crystal 1995b). In vivo systemic, intravenous, intra-arterial and topical modes of administration have proved equally ineffective. Hence, apart from the obvious need to develop more optimal vectors, there is a need to develop better surgical methods for the delivery of genes for the treatment of both genetic and acquired diseases affecting organs, in which cases targeted organ-specific gene transfer is inevitable.