Impact of age and vector construct on striatal and nigral transgene expression

Authors

Nicole K. Polinski, Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USA; Neuroscience Graduate Program, Michigan State University, East Lansing, Michigan, USA.
Fredric P. Manfredsson, Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USA; Mercy Health Saint Mary's, Grand Rapids, Michigan, USA.Follow
Matthew J. Benskey, Department of Translational Science and Molecular Medicine, Michigan State University , Grand Rapids, Michigan, USA.
D Luke Fischer, Department of Translational Science and Molecular Medicine, Michigan State University , Grand Rapids, Michigan, USA.
Christopher J. Kemp, Department of Translational Science and Molecular Medicine, Michigan State University , Grand Rapids, Michigan, USA.
Kathy Steece-Collier, Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USA; Mercy Health Saint Mary's, Grand Rapids, Michigan, USA.
Ivette M. Sandoval, Department of Translational Science and Molecular Medicine, Michigan State University , Grand Rapids, Michigan, USA.
Katrina L. Paumier, Department of Translational Science and Molecular Medicine, Michigan State University , Grand Rapids, Michigan, USA.
Caryl E. Sortwell, Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USA; Mercy Health Saint Mary's, Grand Rapids, Michigan, USA.

Document Type

Article

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, hybridization 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.

Publication Date

1-1-2016

Publication Title

Molecular therapy. Methods & clinical development

ISSN

2329-0501

Volume

3

First Page

16082

PubMed ID

27933309

Digital Object Identifier (DOI)

10.1038/mtm.2016.82

Recommended Citation

Polinski, Nicole K.; Manfredsson, Fredric P.; Benskey, Matthew J.; Fischer, D Luke; Kemp, Christopher J.; Steece-Collier, Kathy; Sandoval, Ivette M.; Paumier, Katrina L.; and Sortwell, Caryl E., "Impact of age and vector construct on striatal and nigral transgene expression" (2016). Translational Neuroscience. 1426.
https://scholar.barrowneuro.org/neurobiology/1426