edifoligide and Arterial-Occlusive-Diseases

Surgical bypass of arterial occlusions using autogenous vein provides an effective treatment for many patients with advanced coronary or peripheral atherosclerosis. However, the long-term benefit of bypass surgery is limited by the development of de novo occlusive lesions within the vein graft, which occurs in a significant percentage of patients over time. The pathophysiology of vein graft failure involves a complex interplay between an acute vascular injury response and the hemodynamic adaptation of the vein to arterial forces. Cell proliferation, inflammation, and matrix metabolism are critical components of postimplantation remodeling. Conventional pharmacotherapy has had limited impact on graft failure. Vein grafts present a unique and attractive opportunity for molecular engineering, which is defined for purposes of this review as the local application of genomic (eg, gene transfer or gene inhibition) or proteomic interventions designed to alter the healing response. The critical enabling technologies for these strategies are described, with a perspective on preclinical and clinical development for this indication. The recently completed clinical trials of edifoligide (E2F decoy oligodeoxynucleotide) provide important lessons for future studies. A better understanding of the remodeling response of vein grafts in humans is required to design effective molecular therapies and to define the appropriate target populations and surrogate markers for future clinical trials.

Topics: Animals; Arterial Occlusive Diseases; Drug Carriers; Gene Transfer Techniques; Genetic Engineering; Genetic Therapy; Genomics; Graft Occlusion, Vascular; Graft Survival; Humans; Oligonucleotides; Proteomics; Tissue Engineering; Transplantation, Autologous; Treatment Outcome; Vascular Patency; Vascular Surgical Procedures; Veins

Longevity of lower-extremity revascularization procedures has typically been limited because of restenosis of grafts, as well as stents and other percutaneous techniques. The ability to prevent or ameliorate neointimal hyperplasia and improve durability of lower-extremity arterial reconstruction is the focus of significant scientific and clinical research. The transcription factor decoy edifoligide was investigated as a potential inhibitor of neointimal hyperplasia, but the results of the pivotal clinical trial did not demonstrate significant improvement in graft reintervention, although secondary patency was improved. Similar to the coronary circulation, drug-eluting stents are a potential tool for prevention of restenosis after percutaneous arterial reconstruction. The SIROCCO study did not demonstrate improvement in superficial femoral artery stent patency with sirolimus-eluting stents. Studies are underway that are investigating paclitaxel-eluting stents for use in the superficial femoral artery. Other potential mediators of restenosis include absorbable drug-eluting stents and antibody-coated stents designed to promote endothelialization of the stent or graft surface. In addition, absorbable wraps eluting paclitaxel can be used at arterial and arteriovenous anastomoses to prevent restenosis. Clinical trials investigating these novel technologies are underway.

Topics: Arterial Occlusive Diseases; Blood Vessel Prosthesis Implantation; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Hyperplasia; Leg; Oligonucleotides; Paclitaxel; Radiography; Tunica Intima; Vascular Patency