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Gene Transfer of an Engineered Transcription Factor Promoting Expression of VEGF-A Protects Against Experimental Diabetic Neuropathy

¹ Faculty of Life Sciences, University of Manchester, Manchester, U.K
² Sangamo Biosciences, Richmond, California
³ Department of Genetics, University of Leicester, Leicester, U.K
⁴ Chiron, Emeryville, California

Address correspondence and reprint requests to S. Kaye Spratt, PhD, 501 Canal Blvd., Suite A100, Richmond, CA 94804. E-mail: kspratt{at}sangamo.com

Abbreviations: CMV, cytomegalovirus; DOX, doxycycline; DMEM, Dulbecco’s modified Eagle’s medium; MNCV, motor NCV; NCV, nerve conduction velocity; NRK, normal rat kidney; SNCV, sensory NCV; STZ, streptozotocin; VEGF, vascular endothelial growth factor; ZFP-TF, zinc finger protein transcription factor

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.

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