Gene transfer of an engineered transcription factor promoting expression of VEGF-A protects against experimental diabetic neuropathy

Sally A. Price, Carolyn Dent, Beatriz Duran-Jimenez, Yuxin Liang, Lei Zhang, Edward J. Rebar, Casey C. Case, Philip D. Gregory, Tyler J. Martin, S. Kaye Spratt, David R. Tomlinson

    Research output: Contribution to journalArticlepeer-review

    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. © 2006 by the American Diabetes Association.
    Original languageEnglish
    Pages (from-to)1847-1854
    Number of pages7
    JournalDiabetes
    Volume55
    Issue number6
    DOIs
    Publication statusPublished - 2006

    Keywords

    • CMV, cytomegalovirus
    • DMEM, Dulbecco's modified Eagle's medium
    • DOX, doxycycline
    • MNCV, motor NCV
    • NCV, nerve conduction velocity
    • NRK, normal rat kidney
    • SNCV, sensory NCV
    • STZ, streptozotocin
    • VEGF, vascular endothelial growth factor

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