Clinical Safety and Preliminary Efficacy of Plasmid pUDK-HGF Expressing Human Hepatocyte Growth Factor (HGF) in Patients with Critical Limb Ischemia

Abstract

Intramuscular injection of pUDK-HGF is safe, and may provide symptomatic relief for CLI patients. A larger, randomized, double blinded phase II trial will provide more information on safety and efficacy.

Gene therapy for neuropathic pain induced by spared nerve injury with naked plasmid encoding hepatocyte growth factor

“…[16][17][18] Previous studies have shown that HGF protected neurons from injury and promoted nerve regeneration in the peripheral and central nervous systems in vivo. 10 Consistent with other clinical results, [23][24][25][26][27] intramuscular injection of pUDK-HGF into the limbs of patients was well tolerated and decreased the mean visual analogue scale value, suggesting that pUDK-HGF attenuated the pain induced by a chronic cutaneous wound. Of note, our clinical trial using a naked plasmid expressing HGF only consisting of 728 amino acids, named as pUDK-HGF, was performed to treat patients with critical limb ischemia.…”

“…9 Subsequently, HGF was reported to have several functions, including angiogenesis, 10 morphogenesis, 11 anti-inflammation 12 and tissue regeneration in a variety of organs, [13][14][15] as well as enhancement of neurite outgrowth from dorsal root ganglia. 9 Subsequently, HGF was reported to have several functions, including angiogenesis, 10 morphogenesis, 11 anti-inflammation 12 and tissue regeneration in a variety of organs, [13][14][15] as well as enhancement of neurite outgrowth from dorsal root ganglia.…”

Hepatocyte growth factor and alternative splice variants - expression, regulation and implications in osteogenesis and bone health and repair

“…Additionally, a recent human phase I clinical trial used intramuscular injections of plasmid encoded HGF (pUDK-HGF) to treat and ameliorate the symptoms of critical limb ischemia. While the study was small (21-patients) and shows varied degrees of symptom reduction between patients, it does set the stage for further phase II trials using plasmid-based HGF 71 .…”

“…There are two identified elimination mechanisms for HGF: receptor-mediated endocytosis through HGF/cMET, and endocytosis through heparin on the cell surface 70 . However, the use of plasmid DNA delivery of HGF has been and is being successfully used in clinical models 71, 74, 75 . There are also reports of HGF being administered via hydrogels 60, 76, 77 and using small molecule mimetics of HGF 78 to produce positive effects in vitro and in vivo .…”

“…Plasmid-based delivery of hHGF should promote (through the p38 pathway) hMSC osteogenic differentiation and offers a safe and effective therapeutic treatment for bone repair. This new technology is currently being used in phase II clinical trials and is shown to be safe and therapeutically beneficial 71, 81, 83–85 . Animal models using naked-plasmid hHGF delivery show safe and efficient transient delivery of exogenous HGF, leading to activation of growth-related signal transduction events and promotion of cell proliferation 84 in a mouse model of liver regeneration.…”