Nonviral Retrograde Gene Transfer of Human Hepatocyte Growth Factor Improves Neuropathic Pain-related Phenomena in Rats

Abstract

Peripheral nerve injury occasionally causes chronic neuropathic pain with hyperalgesia and allodynia. However, its treatment is difficult. Here, we used a chronic constriction injury (CCI) model in rats to investigate the effects on experimental neuropathic pain of the human hepatocyte growth factor (HGF) gene delivered into the nervous system by retrograde axonal transport following its repeated intramuscular transfer, using liposomes containing the hemagglutinating virus of Japan (HVJ). CCI (control) rats exhibited marked mechanical allodynia and thermal hyperalgesia, and decreased blood flow in sciatic nerve and hind paw. All these changes were significantly reversed by HGF gene transfer. In the sciatic nerve in HGF-treated rats, the size-frequency distributions for myelinated and unmyelinated axons each showed a rightward shift, the number of myelinated axons >5 microm in diameter was significantly increased, and the mean diameter of unmyelinated axons was significantly increased (versus CCI rats). Levels of P2X3, P2X4, and P2Y1 receptor mRNAs, and of interleukin-6 (IL-6) and activating transcription factor 3 (ATF3) mRNAs, were elevated in the ipsilateral dorsal root ganglia and/or sciatic nerve by CCI, and these levels were decreased by HGF gene transfer. These results may point toward a potential new treatment strategy for chronic neuropathic pain in this model.

Safety of a non-viral plasmid-encoding dual isoforms of hepatocyte growth factor in critical limb ischemia patients: a phase I study

“…This observation is supported by a rat model in which investigators could demonstrate a significant decrease of pain and increase blood flow in sciatic nerve and hind paw of rats receiving HGF injections. 30 However, owing to the small sample size, this finding remains an observation only and will be closer evaluated in the phase II trial.…”

Genomic Organization of Purinergic P2X Receptors

“…More importantly, an increasing amount of works have proven that P2X represents important therapeutic targets in pathologies as important as chronic pain in cancer and inflammation [58] [59]. With only few selective antagonists available [19], new strategies such as gene therapy can be the more effective choice when it comes to selectively regulate heteromeric P2X activation in cells [60]. In this work we provide a comprehensive depiction of the genomic organization of P2X receptors in the major model species of mammals.…”

Phase 1/2 Open-label Dose-escalation Study of Plasmid DNA Expressing Two Isoforms of Hepatocyte Growth Factor in Patients With Painful Diabetic Peripheral Neuropathy

“…7,8 HGF is also neurotrophic for peripheral sensory, sympathetic, and motor neurons, and it promotes neuronal survival and axonal outgrowth both in vitro and in vivo. [23][24][25][26][27][28][29][30] The combined angiogenic and neurotrophic properties of HGF make it an ideal candidate for the treatment of PDPN. Because HGF has an in vivo half-life of <15 minutes, 31 however, delivery of effective doses of exogenous HGF to target sites for therapeutically meaningful lengths of time is challenging.…”