Vascular endothelial growth factor-induced angiogenic gene therapy in patients with peripheral artery disease

This phase 1 clinical trial tested the safety of intramuscular gene transfer by using naked plasmid DNA encoding the gene for VEGF, and analyzed the potential therapeutic benefits in patients with severe peripheral arterial disease (PAD). This study was an open-labeled, dose- escalating, single-center trial on nine male patients with severe debilitating PAD who had not responded to conventional therapy. Seven had Buerger's disease and two had arteriosclerosis obliterans. Plasmid DNA (pCK) containing human VEGF165 was given by eight intramuscular injections in and around the area in need of new blood vessels. The study evaluated three escalating total doses (2, 4, and 8 mg of pCK- VEGF165), with half of each total dose given four weeks apart. The follow-up duration was nine months. The gene injections were well tolerated without significant side effects or laboratory abnormalities related to gene transfer. Three patients showed transient edema in their extremities. Ischemic pain of the affected limb was relieved or improved markedly in six of seven patients. Ischemic ulcers healed or improved in four of six patients. The mean ankle-brachial index (ABI) improved significantly. Six of nine patients showed an increase in collateral vessels around the injection sites demonstrated by digital subtraction angiography. However, there was no relationship between the degree of ABI improvement and the dose given. Mean plasma levels of VEGF did not increase significantly. In conclusion, intramuscular injections of pCK- VEGF165 can be performed safely to induce therapeutic angiogenesis in patients with severe PAD.

Vascular endothelial growth factor (VEGF)-induced angiogenic gene therapy in a patient with critical limb ischemia / 대한내과학회지

We report VEGF-induced angiogenic gene therapy in a patient with critical limb ischemia, who did not respond to conventional treatment. This patient was the first case in a dose-escalating series of phase I clinical trial. The patient had severe resting pain, gangrene and diffuse ulcer in his left foot. Total 1,000 micro gram of naked DNA encoding human VEGF165 was administered intramuscularly to 8 sites of the left lower extremity. Four weeks after the first 1,000 micro gram injection, a second 1,000 micro gram was administered to the same sites (total dose: 2,000 micro gram). After gene therapy, resting pain gradually reduced and the amount of analgesics taken by the patient decreased. The ischemic wound of lower extremity slightly improved. However, there was no complete wound healing at 12 weeks of treatment. Digital subtraction angiography at 12 weeks after gene therapy showed an increase in collateral vessels at the mid-tibial, ankle and foot arch levels. Immediately and up to 12 weeks, there was no complication related to gene therapy. These findings may be cautiously interpreted to indicate that intramuscular injection of naked plasmid DNA of VEGF165 may induce therapeutic angiogenesis in a patient with critical limb ischemia. Further clinical evaluation of VEGF-induced gene therapy is needed to evaluate the safety and efficiency of this treatment.