title: Recombinant adenoassociated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain.
abstract: Clinical trials are examining the efficacy of viral vector-mediated gene delivery for treating Parkinson's disease. Although viral vector strategies have been successful in preclinical studies, to date clinical trials have disappointed. This may be because of the fact that preclinical studies fail to account for aging. Aging is the single greatest risk factor for developing Parkinson's disease and age alters cellular processes utilized by viral vectors. We hypothesized that the aged brain would be relatively resistant to transduction when compared with the young adult. We examined recombinant adeno-associated virus 2/5-mediated green fluorescent protein (rAAV2/5 GFP) expression in the young adult and aged rat nigrostriatal system. GFP overexpression was produced in both age groups. However, following rAAV2/5 GFP injection to the substantia nigra aged rats displayed 40%-60% less GFP protein in the striatum, regardless of rat strain or duration of expression. Furthermore, aged rats exhibited 40% fewer cells expressing GFP and 4-fold less GFP messenger RNA. rAAV2/5-mediated gene transfer is compromised in the aged rat midbrain, with deficiencies in early steps of transduction leading to significantly less messenger RNA and protein expression.
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Nicole K
authors.initials: NK
authors.lastname: Polinski
authors.affiliation: Graduate Program in Neuroscience, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Gombash
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Fredric P
authors.initials: FP
authors.lastname: Manfredsson
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Lipton
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kemp
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Allyson
authors.initials: A
authors.lastname: Cole-Strauss
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Kanaan
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Steece-Collier
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Kuhn
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Wohlgenant
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA. Electronic address: caryl.sortwell@hc.msu.edu.
authors.forename: Caryl E
authors.initials: CE
authors.lastname: Sortwell
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D008636:Mesencephalon / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis* / Q000235:genetics*; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D011995:Recombination, Genetic
chemical_list: D012333:RNA, Messenger
keywords: Parkinson's disease; Striatum; Substantia nigra; Transduction; Viral vector