186. Long-Term Results of pCMV-vegf165 Intramuscular Gene Transfer in Patients With Chronic Lower Limb Ischemia

Abstract

Restriction of blood flow due to atherosclerosis leads to chronic lower limb ischemia (CLI) affected 3-8% of the general population. Current pharmacological therapies have limited effects. Therefore, developing new treatments is pivotal. Gene therapy is targeted at inducing angiogenesis in ischemic extremities via increased endogenous expression of vascular growth factors. Among many, plasmid DNA vectors play a significant role in gene therapy and are safe with low immunogenicity and no risk of insertional mutagenesis.A novel drug “Neovasculgen” became the first gene therapy for patients with CLI approved by regulatory authorities in Russia in 2011. It contains a plasmid DNA encoding vascular endothelial growth factor VEGF165 (pCMV-vegf165). There was conducted a multicentre randomised controlled clinical trial of the intramuscular transfer of this new gene product in 100 patients with CLI, stage 2a-3 disease according to Fontaine. The trial lasted 6 months. It was concluded that pCMV-vegf165 transfer significantly improved pain-free walking distance (PWD) and caused no adverse effects. Efficacy and safety of this therapy were evaluated and translated into practice. Most of patients enrolled in the trial gave their consent to participate in the long-term follow-up study. The primary endpoint was PWD, the secondary – ankle-brachial index (ABI) and transcutaneous oxygen tension (TcPO2).PWD in patients who received pCMV-vegf165 increased throughout the 3-year follow-up period: by the end of the 1st year the parameter increased by 167.2% as compared to the 135.3 m baseline (p<0.05). The tendency remained positive throughout the following two years of monitoring (Fig. 1Fig. 1). PWD decreased by 27% within a 3-year follow-up period in control patients who received conventional therapy alone (p<0.05).Fig. 1Pain-free walking distance in patients of test (pCMV-vegf165) and control groups.View Large Image | Download PowerPoint SlideChanges in secondary endpoints were less frequent and less pronounced. TcPO2 increased by 14% (10mm Hg) in the pCMV-vegf165 group by the end of the 1st year (p<0.05). The value remained stable during the next two years. TcPO2 slightly decreased in the control patients throughout the 3-year follow-up period. ABI significantly increased in the test group at each time point, but the difference comparing with control was not statistically significant.We conclude that gene therapy stably increases PWD and improves functional state of patients with CLI.