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

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.

Complementary Gene Therapy after Revascularization with the Saphenous Vein in Diabetic Foot Syndrome

“…In 2003, Shyu et al proved that VEGF gene therapy is not only safe but also effective. In the group of patients receiving the gene, the ABI increased significantly, and angio-MR studies showed an improvement in the vascularity of the limbs [43,44].…”

Peripheral inflammatory response in people after acute ischaemic stroke and isolated spontaneous cervical artery dissection

“…Preclinical studies on rats or mice demonstrated the positive effect of HGF on protecting blood–brain barrier integrity, reducing infarct volume, and improving functional recovery after stroke 69 – 72 . Clinical trials testing HGF in peripheral or coronary artery ischaemia proved good tolerance 73 – 75 . However, to our knowledge, such trials for ischaemic stroke have not been conducted yet.…”

LNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing

“…To explore the therapeutic potential of ASCs engineered by DIM1T-SEC LNPs in diabetic cutaneous wounds, we constructed saRNAs encoding hepatocyte growth factor (HGF) to generate therapeutic proteinhypersecreting ASCs. Previous studies reported that HGF can regulate cellular migration, proliferation, and morphogenesis in many types of cells at wound sites, thereby promoting epithelial repair and neovascularization during wound healing 52,53 . The short half-life of HGF (<3-5 min) in plasma, however, may require repeated administrations to maintain therapeutic windows in clinical applications.…”