title: Neuroprotection using gene therapy to induce vascular endothelial growth factor-A expression.
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.
authors.affiliation: Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Sakowski
authors.forename: S B
authors.initials: SB
authors.lastname: Heavener
authors.forename: J S
authors.initials: JS
authors.lastname: Lunn
authors.forename: K
authors.initials: K
authors.lastname: Fung
authors.forename: S S
authors.initials: SS
authors.lastname: Oh
authors.forename: S K
authors.initials: SK
authors.lastname: Spratt
authors.forename: N D
authors.initials: ND
authors.lastname: Hogikyan
authors.forename: E L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D009045:Motor Endplate / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology*; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D061226:Recurrent Laryngeal Nerve Injuries; D014162:Transfection; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D014826:Vocal Cord Paralysis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D014827:Vocal Cords / Q000502:physiology; D016335:Zinc Fingers / Q000235:genetics
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A