With the continuing refinement of recombinant DNA techniques, the concept of human gene therapy has moved from a theoretic axis to the actual transfer of genes into the somatic cells of patients.<sup>20Grossman M., Raper S.E., Kozarsky K., e al. Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolemia Nat Genet 1994 ;  6 : 337

Cliccare qui per andare alla sezione Riferimenti</sup> The concept itself is rather straightforward and involves the insertion of genes into cells for the expressed intent of correcting an inborn genetic error or creating a new cellular function. In such a context, DNA has the potential to become the “drug” of choice.

There are two general categories of gene delivery systems, or vectors as they are commonly called: viral and nonviral vectors. Of the 210 gene therapy protocols that have been approved for phase I clinical trials, approximately 80% utilize virus vectors.<sup>37Recombinant DNA Advisory Committee (RAC) Committee Report: Human Gene Therapy Protocols, 9-17-97.

Cliccare qui per andare alla sezione Riferimenti</sup> Despite the fact that virally derived vectors have many of the characteristics of the parent viruses themselves, and despite the fact that some of these viruses may be pathogens in their normal state, it remains that viruses have evolved a number of very efficient mechanisms to assure that replication occurs. One of the most important characteristics is the ability of the virus to assure transport of its genomic DNA to the nucleus of the host cell without degradation by lysosomes.<sup>45Seth P., Fitzgerald D., Ginsberg H., e al. Evidence that the penton base of adenovirus is involved in potentiation of toxicity of Pseudomonas exotoxins conjugated to epidermal growth factor Mol Cell Biol 1984 ;  4 : 1528

Cliccare qui per andare alla sezione Riferimenti</sup> It has become clear that one can take advantage of some of the barriers to gene expression by using viruses as the delivery vehicles, and this is discussed in more detail later.

Included among the nonviral vector systems are direct DNA delivery, liposomes, and DNA–protein complexes. Each of these systems has certain kinds of advantages. For example, such vectors can be more easily prepared in a uniform fashion and can be made in relatively unlimited quantities; almost none of these compounds invoke an inflammatory response. A number of factors, however, may contribute to a reduced efficiency of expression. There may be competitive uptake by cells of the reticuloendothelial system when such cells are not the target cells of choice, and some types of liposomes are subject to nonspecific binding by a large range of different cell types.

Currently, all of the available delivery systems, both viral and nonviral, suffer specific types of shortcomings. Yet there are abundant data to indicate that such systems can be successfully manipulated by changing surface recognition components, deleting certain structural genes, or inserting transcriptional elements that favor gene expression in certain restricted target cells.<sup>32Miller N., Vile R. Targeted vectors for gene therapy FASEB J 1995 ;  9 : 190

Cliccare qui per andare alla sezione Riferimenti</sup> A description of the major vector systems, both in use and in development, is the subject of this discussion.