title: Impact of age and vector construct on striatal and nigral transgene expression.
abstract: Therapeutic protein delivery using viral vectors has shown promise in preclinical models of Parkinson's disease (PD) but clinical trial success remains elusive. This may partially be due to a failure to include advanced age as a covariate despite aging being the primary risk factor for PD. We investigated transgene expression following intracerebral injections of recombinant adeno-associated virus pseudotypes 2/2 (rAAV2/2), 2/5 (rAAV2/5), 2/9 (rAAV2/9), and lentivirus (LV) expressing green fluorescent protein (GFP) in aged versus young adult rats. Both rAAV2/2 and rAAV2/5 yielded lower GFP expression following injection to either the aged substantia nigra or striatum. rAAV2/9-mediated GFP expression was deficient in the aged striatonigral system but displayed identical transgene expression between ages in the nigrostriatal system. Young and aged rats displayed equivalent GFP levels following LV injection to the striatonigral system but LV-delivered GFP was deficient in delivering GFP to the aged nigrostriatal system. Notably, age-related transgene expression deficiencies revealed by protein quantitation were poorly predicted by GFP-immunoreactive cell counts. Further,in situhybridization for the viral CβA promoter revealed surprisingly limited tropism for astrocytes compared to neurons. Our results demonstrate that aging is a critical covariate to consider when designing gene therapy approaches for PD.
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USA; Neuroscience Graduate Program, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Nicole K
authors.initials: NK
authors.lastname: Polinski
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USA; Mercy Health Saint Mary's, Grand Rapids, Michigan, 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, Michigan, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Benskey
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University , Grand Rapids, Michigan, USA.
authors.forename: D Luke
authors.initials: DL
authors.lastname: Fischer
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University , Grand Rapids, Michigan, 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, Michigan, USA; Mercy Health Saint Mary's, Grand Rapids, Michigan, 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, Michigan, USA.
authors.forename: Ivette M
authors.initials: IM
authors.lastname: Sandoval
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University , Grand Rapids, Michigan, USA.
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Paumier
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USA; Mercy Health Saint Mary's, Grand Rapids, Michigan, USA.
authors.forename: Caryl E
authors.initials: CE
authors.lastname: Sortwell