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Neuroprotection using gene therapy to induce vascular endothelial growth factor-A expression

Gene Therapy volume 16, pages 1292–1299 (2009)Cite this article

Abstract

Engineered zinc-finger protein (ZFP) transcription factors induce the expression of endogenous genes and can be remotely delivered using adenoviral vectors. One such factor, Ad-32Ep65-Flag (Ad-p65), targets and induces expression of vascular endothelial growth factor (VEGF; also called VEGF-A) splice variants in their normal biological stoichiometry. We show that Ad-p65 transfection of primary motor neurons results in VEGF variant expression and a significant increase in axon outgrowth in these cells. Given the neuroprotective effects of VEGF and its ability to increase neurite outgrowth, we examined the efficacy of Ad-p65 to enhance motor neuron regeneration in vivo using rats that have undergone recurrent laryngeal nerve (RLN)-crush injury. Injection of Ad-p65 after RLN crush accelerated the return of vocal fold mobility and the percentage of nerve-endplate contacts in the thyroarytenoid muscle. Overall, adenoviral delivery of an engineered ZFP transcription factor inducing VEGF-A splice variant expression enhances nerve regeneration. ZFP transcription factor gene therapy to increase expression of the full complement of VEGF-A splice variants is a promising avenue for the treatment of nerve injury and neurodegeneration.

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Acknowledgements

We thank the A. Alfred Taubman Medical Research Institute and the Program for Neurology Research and Discovery for supporting our research. SAS is supported by NIH T32 NS007222-26. We also thank Ms Judith Boldt for excellent secretarial support during the preparation of this paper.

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Author notes

  1. S B Heavener

    Present address: 5Current address: Carolina Ear, Nose and Throat Head and Neck Surgery Center, Hickory, NC, USA.,

Authors and Affiliations

  1. Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI, USA

    S A Sakowski, J S Lunn, S S Oh & E L Feldman

  2. Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA

    S B Heavener & N D Hogikyan

  3. Department of Otolaryngology, University of Western Ontario, London, Ontario, Canada

    K Fung

  4. Sangamo BioSciences, Inc., Richmond, CA, USA

    S K Spratt

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Correspondence to E L Feldman.

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Sakowski, S., Heavener, S., Lunn, J. et al. Neuroprotection using gene therapy to induce vascular endothelial growth factor-A expression. Gene Ther 16, 1292–1299 (2009). https://doi.org/10.1038/gt.2009.111

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