Double VEGF/HGF gene therapy in critical limb ischemia complicated by diabetes mellitus

Work from Polish colleagues Barc and coworkers report promise with a novel gene therapy approach. Critical leg ischemia (CLI) complicated by diabetes mellitus (DM), which is a very common and dangerous disease, represents the ultimate stage of peripheral arterial disease. Patients are treated with antiplatelet drugs, statins and limb revascularization, but a significant number of patients are not candidate for revascularization.

diabetes mellutis

Abstract

Critical leg ischemia (CLI) complicated by diabetes mellitus (DM), which is a very common and dangerous disease, represents the ultimate stage of peripheral arterial disease. Patients are treated with antiplatelet drugs, statins and limb revascularization, but a significant number of patients are not candidate for revascularization. Literature shows that in such cases, gene therapy could be a perfect therapeutic option. The aim of our study was to evaluate efficacy of double vascular endothelial growth factor/hepatocyte growth factor (VEGF/HGF) gene therapy in patients with CLI complicated by DM. We observed that 90 days after administration, serum level of VEGF and ankle-brachial index increased significantly (p < 0.001) and rest pain decreased significantly compared with the control group (p < 0.002). Moreover considerable improvement in vascularization was observed in computed tomography angiography (P = 0.04). Based on the results of this study, we suggest that the therapy with pIRES/VEGF165/HGF bicistronic plasmid administration is a safe and effective method of treatment of patients with both CLI and diabetes Mellitus (DM).

Introduction

Critical leg ischemia (CLI) indicates the final stage of peripheral arterial disease (PAD). Due to the fact that CLI is most commonly caused by atherosclerosis obliterans, it is heavily associated with smoking and diabetes mellitus (DM) [5617]. PAD leads to approximately 500–1000 new cases of CLI per million people per year and it touches men three times more often than women [1,2,35617]. Revascularization is a cornerstone of therapy to prevent limb amputation, and despite advance in both open and endovascular surgery, many patients are doomed to leg dismemberment. The facts that about one-third of people suffering from CLI in United States are poor or no-option patients and that 30% of CLI patients have to undergo leg amputation with mortality rate of 20% or higher show that this disease makes serious problem nowadays [3,4,5,6,71317]. Because there is no directly CLI aimed medication, the only cure for “not candidate for revascularisation” (NCR) patients is oral antiplatelet drugs, statins, treatment of DM and smoking cessation. Nevertheless, this patients’ cohort has a particularly poor prognosis, including a 1 year amputation rate of 40% and a mortality as high as 20% [4,5,6]. [Read More]

Results

Clinical Follow-Up

Intramuscular injections of bicistronic plasmid were administrated to 14 patients of group 1. The therapy was well tolerated and there were no major complications. Several minor complications occurred within 24 h following injections: tenderness at the injection sites (two patients) and fever (three patients). During our study, all the patients from both groups had no significant changes in laboratory parameters; none of them was hospitalized during follow-up. Some of the patients obtained surgical debridement of necrotic tissue. Two patients on group 1 and four patients in group 2 required limb amputation because of advanced CLI (necrosis, wide ulcerations and severe infection). [Read more]

Discussion

CLI is a life-limiting and life-threatening condition, which is mainly treated by risk factor modification and revascularization [15]. However, a large number of patients are NCR. In these cases, when pharmacological treatment is ineffective or insufficient, double VEGF/HGF gene therapy might be an attractive option. It is well known that VEGF, HGF, or FGF are key factors in the process of proliferation and revascularization [11]. We know that these molecules are produced in case of ischemia and their level depends on intensity of the process [26]. Our therapy leads to an increase in the level of proangiogenic factors in affected tissues. As alluded previously, there are studies showing that the release of HGF to extracellular matrix increases the activity of VEGF during neoangiogenesis [22025]. Based on the evidence outlined above, we believe that double gene therapy has the potential to be more efficient than the single gene therapy. [Read More]

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