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 language | English |
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Pages (from-to) | 1847-1854 |
Number of pages | 7 |
Journal | Diabetes |
Volume | 55 |
Issue number | 6 |
DOIs | |
Publication status | Published - 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