Beperminogene perplasmid for the treatment of critical limb ischemia.

Therapeutic angiogenesis for the treatment of ischemic disease can be attained through the delivery of recombinant growth factor proteins, through gene transfer or cell transplantation. Gene transfer associated with adenovirus or naked plasmid DNAs has been extensively studied in clinical trials. An investigational product, beperminogene perplasmid, is the naked plasmid DNA encoding the cDNA of human HGF, which has potent angiogenic activity. In several clinical trials, beperminogene perplasmid showed favorable safety and efficacy profile in the treatment of critical limb ischemia. This article reviews the results of pre-clinical and clinical studies of beperminogene perplasmid in the treatment of critical limb ischemia caused by peripheral arterial disease and Buerger's disease.

Novel anti-microbial peptide SR-0379 accelerates wound healing via the PI3 kinase/Akt/mTOR pathway.

We developed a novel cationic antimicrobial peptide, AG30/5C, which demonstrates angiogenic properties similar to those of LL-37 or PR39. However, improvement of its stability and cost efficacy are required for clinical application. Therefore, we examined the metabolites of AG30/5C, which provided the further optimized compound, SR-0379. SR-0379 enhanced the proliferation of human dermal fibroblast cells (NHDFs) via the PI3 kinase-Akt-mTOR pathway through integrin-mediated interactions. Furthermore SR-0379 promoted the tube formation of human umbilical vein endothelial cells (HUVECs) in co-culture with NHDFs. This compound also displays antimicrobial activities against a number of bacteria, including drug-resistant microbes and fungi. We evaluated the effect of SR-0379 in two different would-healing models in rats, the full-thickness defects under a diabetic condition and an acutely infected wound with full-thickness defects and inoculation with Staphylococcus aureus. Treatment with SR-0379 significantly accelerated wound healing when compared to fibroblast growth factor 2 (FGF2). The beneficial effects of SR-0379 on wound healing can be explained by enhanced angiogenesis, granulation tissue formation, proliferation of endothelial cells and fibroblasts and antimicrobial activity. These results indicate that SR-0379 may have the potential for drug development in wound repair, even under especially critical colonization conditions.

Hepatocyte growth factor stimulated angiogenesis without inflammation: differential actions between hepatocyte growth factor, vascular endothelial growth factor and basic fibroblast growth factor.

Based on the potent angiogenic effects of hepatocyte growth factor (HGF), therapeutic angiogenesis using human HGF plasmid DNA increased tissue perfusion and reduced symptoms in patients with critical limb ischemia (CLI) in randomized placebo-controlled clinical trials. To explore further the potent angiogenic activity of HGF, the present study compared the effects of HGF, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) on angiogenesis and vascular inflammation. All of HGF, VEGF and bFGF significantly induced the formation of capillary blood vessel and granulation tissue in the rat paper disc model as an in vivo animal model of angiogenesis. However, although HGF, bFGF and VEGF significantly increased the growth of vascular endothelial cells, bFGF alone, but not HGF or VEGF, significantly increased the growth of vascular smooth muscle cells (VSMCs) in the in vitro proliferation assay. In addition, bFGF, but not HGF or VEGF, significantly activated an essential transcription factor for inflammation, NFκB, and gene expression of its downstream inflammation-related cytokines (IL-8 and MCP-1) in VSMCs, accompanied by an increase in the vascular permeability in the rat paper disc model. Thus, the present results indicated that HGF induced angiogenesis without vascular inflammation, different from bFGF and VEGF. These different properties between HGF, VEGF and bFGF might affect the efficiency of therapeutic angiogenesis.