Therapeutic angiogenesis in ischemic limbs.

Abstract

In this issue of Circulation , Baumgartner et al1 ). The plasmid DNA was injected directly into the muscle of ischemic limbs. Anatomic and functional efficacy was demonstrated by increased serum levels of VEGF, improved hemodynamic measurements and angiographic evaluation, reduced pain, increased healing of ischemic ulcers, limb salvage, and immunohistochemical evidence of proliferating endothelial cells in tissue specimens. The authors emphasize that this is the first medical therapy to achieve an increase in limb perfusion that is equivalent to or greater than successful surgical or percutaneous intervention. Direct intramuscular gene transfer of plasmid DNA appears to effectively stimulate collateral vessel growth, despite the lower transfection efficiency that is usually associated with gene therapy in the absence of a viral vector. This result has implications for other clinical trials of gene therapy that use intramuscular naked DNA. The fact that Isner’s group could prepare the plasmid for human use in a university medical center laboratory dedicated to this purpose reveals why gene therapy has moved so rapidly from the laboratory to the clinic, in contrast to protein therapy, which requires expensive manufacturing facilities and years of scale-up effort. Although the plasmid was injected into muscle of the ischemic limb, VEGF levels were apparently elevated in the whole circulation, as evidenced by transient peaks of VEGF in the serum and by edema of the ischemic limb and in some patients, in the opposite limb. The increased collateral vessels, however, are localized to the ischemic limb and do not develop in other areas of the body. This may reflect in part the short half-life of VEGF in the circulation (minutes) as well as the upregulation of receptors for VEGF in ischemic tissue. …