Direct gene transfer for the understanding and treatment of human disease

Direct gene transfer has been used to develop molecular genetic interventions for acquired diseases in several animal models. Through the use of intravascular catheters or anatomically localized injection of DNA liposome complexes, specific tissues can be transduced with recombinant genes. Several promising applications of this method for the study of vascular biology have been demonstrated by direct gene transfer into arteries in vivo. Delivery, via catheter, of genes that modulate the thrombogenic or proliferative properties of vascular cells may someday provide therapy for stenotic lesions of atherosclerosis or following angioplasty. Cancer is another acquired disorder in which direct gene transfer may improve the efficacy of treatment. Introduction of class I MHC or cytokine genes with antitumor or immunostimulatory effects have demonstrated promise in animal models. Direct transfer of an allogeneic class I MHC gene into tumors in vivo induces a CD8⁺ CTL response against weak antigens on poorly immunogenic tumors. The efficacy of this antitumor response can be augmented to induce regression of actively growing established tumors. Additional strategies, such as intratumoral delivery of combinations of multiple cytokine and MHC genes, may serve to improve the antitumor response. A clinical gene therapy protocol is underway to analyze the safety and efficacy of DNA liposome-mediated gene transfer in humans. Development of improved gene delivery systems and introduction of recombinant genes into visceral tumors by intravascular catheter will extend the application of direct gene transfer to immunotherapy of malignancies. These clinical trials of direct gene transfer will help to develop new treatment strategies for human diseases.