Two-Stage Gene Therapy (VEGF, HGF and ANG1 Plasmids) as Adjunctive Therapy in the Treatment of Critical Lower Limb Ischemia in Diabetic Foot Syndrome

Int J Environ Res Public Health. 2022 Oct 6;19(19):12818. doi: 10.3390/ijerph191912818.

Abstract

One of the most serious problems in people with diabetes is diabetic foot syndrome. Due to the peripheral location of atherosclerotic lesions in the arterial system of the lower extremities, endovascular treatment plays a dominant role. However, carrying out these procedures is not always possible and does not always bring the expected results. Gene therapy, which stimulates angiogenesis, improves not only the inflow from the proximal limb but also the blood redistribution in individual angiosomes. Due to the encouraging results of sequential treatment consisting of intramuscular injections of VEGF/HGF bicistronic plasmids followed by a month of ANG1 plasmids, we decided to use the described method for the treatment of critical ischemia of the lower limbs in the course of diabetes and, more specifically, in diabetic foot syndrome. Twenty-four patients meeting the inclusion criteria were enrolled in the study. They were randomly divided into two equal groups. The first group of patients was subjected to gene therapy, where the patients received intramuscular injections of pIRES/VEGF165/HGF plasmids and 1 month of ANG-1 plasmids. The remaining patients constituted the control group. Gene therapy was well tolerated by most patients. The wounds healed significantly better in Group 1. The minimal value of ABI increased significantly in Group 1 from 0.44 ± 0.14 (± standard deviation) to 0.47 ± 0.12 (with p = 0.028) at the end of the study. There were no significant differences in the control group. In the gene treatment group, PtcO2 increased significantly (from 28.71 ± 10.89 mmHg to 33.9 ± 6.33 mmHg with p = 0.001), while in Group 2, no statistically significant changes were found. The observed resting pain decreased significantly in both groups (Group 1 decreased from 6.80 ± 1.48 to 2.10 ± 1.10; p < 0.001; the control group decreased from 7.44 ± 1.42 to 3.78 ± 1.64 with p < 0.001). In our study, we evaluated the effectiveness of gene therapy with the growth factors described above in patients with CLI in the course of complicated DM. The therapy was shown to be effective with minimal side effects. No serious complications were observed.

Keywords: ANG1; HGF; VEGF; gene therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diabetes Mellitus* / therapy
  • Diabetic Foot* / drug therapy
  • Genetic Therapy / adverse effects
  • Genetic Therapy / methods
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / therapeutic use
  • Humans
  • Ischemia / therapy
  • Lower Extremity / blood supply
  • Plasmids / genetics
  • Plasmids / therapeutic use
  • Vascular Endothelial Growth Factor A / genetics

Substances

  • HGF protein, human
  • Vascular Endothelial Growth Factor A
  • Hepatocyte Growth Factor

Grants and funding

This publication is part of the project “WroVasc—Integrated Cardiovascular Centre”, co-financed by the European Regional Development Fund, within the Innovative Economy Operational Program of 2007–2013 realized in the Regional Specialist Hospital, Research and Development Center in Wroclaw. The “European Funds—for the Development of Innovative Economy” project was supported by Wroclaw Centre of Biotechnology as part of the program of the Leading National Research Centre (KNOW) for 2014–2018.