title: Gene transfer of an engineered transcription factor promoting expression of VEGF-A protects against experimental diabetic neuropathy.
abstract: Peripheral neuropathy is a common, irreversible complication of diabetes. We investigated whether gene transfer of an engineered zinc finger protein transcription factor (ZFP-TF) designed to upregulate expression of the endogenous vascular endothelial growth factor (VEGF)-A gene could protect against experimental diabetic neuropathy. ZFP-TF-driven activation of the endogenous gene results in expression of all of the VEGF-A isoforms, a fact that may be of significance for recapitulation of the proper biological responses stimulated by this potent neuroprotective growth factor. We show here that this engineered ZFP-TF activates VEGF-A in appropriate cells in culture and that the secreted VEGF-A protein induced by the ZFP protects neuroblastoma cell lines from a serum starvation insult in vitro. Importantly, single and repeat intramuscular injections of formulated plasmid DNA encoding the VEGF-A-activating ZFP-TF resulted in protection of both sensory and motor nerve conduction velocities in a streptozotocin-induced rat model of diabetes. These data suggest that VEGF-A-activating ZFP-TFs may ultimately be of clinical utility in the treatment of this disease.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Price
authors.forename: Carolyn
authors.initials: C
authors.lastname: Dent
authors.forename: Beatriz
authors.initials: B
authors.lastname: Duran-Jimenez
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Liang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Rebar
authors.forename: Casey C
authors.initials: CC
authors.lastname: Case
authors.forename: Philip D
authors.initials: PD
authors.lastname: Gregory
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Martin
authors.forename: S Kaye
authors.initials: SK
authors.lastname: Spratt
authors.forename: David R
authors.initials: DR
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D003929:Diabetic Neuropathies / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D013311:Streptozocin / Q000633:toxicity; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D016895:Culture Media, Serum-Free; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D013311:Streptozocin