ABSTRACT
Over the last decade, gene therapy has attracted considerable interest as a potential approach to organ transplantation. In fact, transplantation offers the unique opportunity of delivering a therapeutic gene to the donor organ after procurement before engraftment. Consequendy, gene delivery to the donor organ is carried out ex vivo during the preservation time under well-controlled conditions.3 This opportunity obviates the need for technically difficult in vivo gene delivery protocols, which often achieve only sub-optimal gene transfer efficiencies. As an example, the catheter-based infusion of a gene containing solution into a coronary artery in vivo is limited by a short dwelling time of the delivered gene in the coronary circulation, as blood flow can only be interrupted for a short time («1 minute). In a pig model o f adenovirus-mediated in vivo gene transfer into the heart, the cardiac uptake of the delivered gene after intracoronary administration was «7-fold lower than after direct intramyocardial injection.4 Low cardiac uptake correlates with increased amounts o f the vector that pass through the coronary circulation and are disseminated systemically. Conversely, ex vivo gene delivery to the donor organ during the preservation time results in the production of high amounts of the therapeutic factor at the very site where the protective effect is needed. The case for local immunosuppression of organ transplants, independent of gene therapy, was discussed some 20 years ago.5 However, gene transfer technologies offer the additional opportunity of producing the therapeutic factor for extended periods of time, potentially even for a lifetime. Clearly, this is an appealing aspect in transplantation as a lifelong condition. In the case when the protective factor is a secreted peptide, gene therapy may be viewed as an alternate approach to the systemic administration of the recombinant peptide. However, many peptides have short half-lives in vivo and require daily injections over long periods of time. In contrast, a single dose of the encoding gene can achieve sustained production and release o f the peptide in vivo. In the case when the therapeutic factor is an intracel lular protein, administration of the recombinant protein is not feasible and gene transfer-based approaches are mandatory.
