Gene-based therapies for restenosis

Multifactorial hypotheses of the pathophysiology of restenosis have led to various mechanism-based gene therapy targets. Thrombosis, vascular injury-induced responses, and increased smooth muscle cell migration and proliferation in the restenotic lesions are the main targets for DNA and antisense oligonucleotide approaches. Various standard techniques of gene transfer used in vitro in tissue culture have also been investigated for in vivo vascular gene transduction. These techniques include simple plasmid DNA solutions, liposome facilitated gene transfer, and various viral vectors using replication defective viruses (adenovirus and retrovirus). Although vascular gene transfer has been demonstrated with various techniques, the optimal target genes of interest to inhibit restenotic process have remained difficult to identify. Success thus far in experimental studies with gene therapy approaches for restenosis have been demonstrated with both cytotoxic approaches, employing a 'suicide gene' administration, using thymidine kinase and ganciclovir; cytostatic approaches interfering with the retinoblastoma gene product cell cycle effects. In addition, antisense oligonucleotides against the proto-oncogenes, c-myb and c-myc have also demonstrated successful inhibition of stenosis in experimental models. It is hypothesized that future strategies will focus on a mechanism of restenosis and optimized gene administration and synergy. In addition, ideal gene transfer methodologies may utilize emerging non-viral approaches, such as polymer-based carrier systems employing biodegradable nanoparticles. Such approaches employing local delivery carrier systems, able to produce local expression of derived gene products, will ultimately lead to optimal treatments for restenosis.