Gene therapy for peripheral arterial disease.
BACKGROUND
Gene therapy has emerged as a novel therapy to promote angiogenesis in patients with critical limb ischemia (CLI) caused by peripheral artery disease. Researchers working in this area have focused on pro-angiogenic factors, such as VEGF, fibroblast growth factor (FGF) and hepatocyte growth factor (HGF). Based on the elaborate studies and favorable results of basic research using naked plasmid DNA (pDNA) encoding these growth factors, some clinical Phase I and Phase II trials have been performed. The results of these studies demonstrate the safety of these approaches and their potential for symptomatic improvement in CLI patients. However, the Phase III clinical trials have so far been limited to HGF gene therapy. Because one pitfall of the Phase III trials has been the limited transgene expression achieved using naked pDNA alone, the development of more efficient gene transfer systems, such as ultrasound microbubbles and the needleless injector, as well as the addition of other genes will make these novel therapies more effective and ease the symptoms of CLI.


METHODS
This study reviews the previously published basic research and clinical trials that have studied VEGF, FGF and HGF gene therapies for the treatment of CLI. Adjunctive therapies, such as the addition of prostacyclin synthase genes and the development of more efficient gene transfer techniques for pDNA, are also reviewed.


CONCLUSIONS
To date, clinical studies have demonstrated the safety of gene therapy in limb ischemia but the effectiveness of this treatment has not been determined. Larger clinical studies, as well as the development of more effective gene therapy, are needed to achieve and confirm beneficial effects.
Osaka University, Kanazawa University and Hamamatsu University School of Medicine, United Graduate School of Child Development, Division of Vascular Medicine and Epigenetics, Department of Child Development , Suita , Japan.
Munehisa
M
Shimamura
Hironori
H
Nakagami
Yoshiaki
Y
Taniyama
Ryuichi
R
Morishita
D000818:Animals; D002986:Clinical Trials as Topic; D005346:Fibroblast Growth Factors / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000628:therapy; D035002:Lower Extremity / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000235:genetics; D058729:Peripheral Arterial Disease / Q000235:genetics / Q000628:therapy*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors; D017228:Hepatocyte Growth Factor
VEGF; angiogenesis; cell-based therapy; fibroblast growth factor; gene therapy; hepatocyte growth factor