Recombinant growth factor gene expression in vascular cells in vivo.
Several issues are important to the use of direct gene transfer as an investigative tool and as a potential therapeutic modality (Table 3). Transfection efficiencies of different vectors must be improved and optimized. Retroviral vectors and DNA liposome conjugates currently used in animal models are low-efficiency vectors. Adenoviruses and adenoviral conjugates appear promising, but issues related to gene persistence, germ-line transmission, and stability of expression must be explored. Second, the pharmacology or dose-response properties of recombinant gene expression have not been investigated. It is not currently known how many cells must be transfected in an arterial segment in order to produce a desired biological effect. Our studies suggest that only a small population of cells is required to secrete a recombinant gene product into the local milieu. This gene product may then have local paracrine effects with amplification of the biological response, suggesting a "gain of function." Third, methods must be developed to target recombinant genes specifically to endothelial cells or smooth muscle cells using cell-specific promoters. Finally, gene expression should be regulated through inducible or repressible promoters. Nonetheless, during the past ten years a dramatic expansion in the fields of gene transfer and gene therapy has occurred. We have entered a new era in which molecular genetic techniques are being increasingly used to investigate the pathophysiology of cardiovascular disorders and to design potential therapies for these diseases. Although technical hurdles related to optimization of vectors and regulated gene expression must be solved, molecular genetic approaches will be increasingly used to study and treat cardiovascular diseases.
Nabel
E G
EG
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0688.
Plautz
G E
GE
Nabel
G J
GJ
D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006133:Growth Substances / Q000096:biosynthesis*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D010957:Plasmids; D011994:Recombinant Proteins / Q000096:biosynthesis*; D012190:Retroviridae
D006133:Growth Substances; D011994:Recombinant Proteins