Prevention of Diabetic Neuropathy by Regulatable Expression of HSV-Mediated Erythropoietin

Abstract

Previous studies have demonstrated that gene transfer of genes coding for neurotrophic factors to the dorsal root ganglion (DRG) using nonreplicating herpes simplex virus (HSV)-based vectors injected subcutaneously can prevent the progression of diabetic neuropathy. Because prolonged expression of neurotrophic factors could potentially have unwanted adverse effects, we constructed a nonreplicating HSV vector, vHrtEPO, to express erythropoietin (EPO) under the control of a tetracycline response element (TRE)-minimal cytomegalovirus (CMV) fusion promoter. Primary DRG neurons in culture infected with vHrtEPO express and release EPO in response to exposure to doxycycline (DOX). Animals infected with vHrtEPO by footpad inoculation demonstrated regulated expression of EPO in DRG under the control of DOX administered by gavage. Mice rendered diabetic by injection of streptozotocin (STZ), inoculated with vHrtEPO, and treated with DOX 4 days out of 7 each week for 4 weeks were protected against the development of diabetic neuropathy as assessed by electrophysiologic and behavioral measures. These studies indicate that intermittent expression of EPO in DRG achieved from a regulatable vector is sufficient to protect against the progression of neuropathy in diabetic animals, and provides proof-of-principle preclinical evidence for the development of such vectors for clinical trial.

Prophylactic L-arginine and ibuprofen delay the development of tactile allodynia and suppress spinal miR-155 in a rat model of diabetic neuropathy

“…Few substances were suggested, such as glutathione 65 , gamma linolenic acid 66 , tolrestat 67 and regulatable expression of HSV-mediated erythropoietin 68 . To our knowledge, none of these substances was translated into a prophylactic drug to be used in patient care, due to either adverse effects or impractical setting.…”

Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative–nitrosative stress and p38 MAPK activation

“…Diabetic peripheral neuropathy (DPN)-related research during the last 20–30 years led to identification of multiple pathogenetic mechanisms including, but not limited to, increased aldose reductase (AR) activity (Ho et al, 2006; Obrosova et al, 2002; Yagihashi et al, 2001), non-enzymatic glycation/glycooxidation (Bierhaus et al, 2004; Cameron et al, 2005; Toth et al, 2008), activation of protein kinase C (Cameron et al, 1999; Nakamura et al, 1999) and mitogen-activated protein kinases [MAPKs (Du et al, 2010; Purves et al, 2001)], oxidative-nitrosative stress (Cameron et al, 2001; Coppey et al, 2001b; Nagamatsu et al, 1995; Obrosova et al, 2005; Schmeichel et al, 2003), C-peptide deficiency (Sima et al,2008; Stevens et al, 2004) and impaired neurotrophic support (Chattopadhyay et al, 2005; Christianson et al, 2007; Francis et al, 2009; Goss et al, 2002; Nakae et al, 2006; Wu et al, 2011), which contribute to this devastating complication of diabetes mellitus. Unfortunately, all monotherapies for DPN studied so far, including AR and protein kinase C inhibitors, acetyl carnitine, nerve growth factor, and the antioxidant α–lipoic acid, showed modest efficacy in clinical trials, or have been abandoned due to adverse side effects (Tesfaye et al, 2010).…”

The effect of erythropoietin application on erythrocyte Na,K- ATPase activities in patients with diabetic polyneuropathy

“…Wu et al demonstrated that intermittent expression of EPO in DRG (Dorsal Root Ganglion) achieved from a regulatable vector is sufficient to protect against the progression of neuropathy in diabetic animals [26 ].…”