Impact of age and vector construct on striatal and nigral transgene expression
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 i...
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doaj-b5c21ac0c35c4056a4ceb135f2ad599d2020-11-24T21:34:43ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012016-01-013C10.1038/mtm.2016.82Impact of age and vector construct on striatal and nigral transgene expressionNicole K Polinski0Fredric P Manfredsson1Matthew J Benskey2D Luke Fischer3Christopher J Kemp4Kathy Steece-Collier5Ivette M Sandoval6Katrina L Paumier7Caryl E Sortwell8Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USATherapeutic 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 situ 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.http://www.sciencedirect.com/science/article/pii/S2329050117300402 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nicole K Polinski Fredric P Manfredsson Matthew J Benskey D Luke Fischer Christopher J Kemp Kathy Steece-Collier Ivette M Sandoval Katrina L Paumier Caryl E Sortwell |
spellingShingle |
Nicole K Polinski Fredric P Manfredsson Matthew J Benskey D Luke Fischer Christopher J Kemp Kathy Steece-Collier Ivette M Sandoval Katrina L Paumier Caryl E Sortwell Impact of age and vector construct on striatal and nigral transgene expression Molecular Therapy: Methods & Clinical Development |
author_facet |
Nicole K Polinski Fredric P Manfredsson Matthew J Benskey D Luke Fischer Christopher J Kemp Kathy Steece-Collier Ivette M Sandoval Katrina L Paumier Caryl E Sortwell |
author_sort |
Nicole K Polinski |
title |
Impact of age and vector construct on striatal and nigral transgene expression |
title_short |
Impact of age and vector construct on striatal and nigral transgene expression |
title_full |
Impact of age and vector construct on striatal and nigral transgene expression |
title_fullStr |
Impact of age and vector construct on striatal and nigral transgene expression |
title_full_unstemmed |
Impact of age and vector construct on striatal and nigral transgene expression |
title_sort |
impact of age and vector construct on striatal and nigral transgene expression |
publisher |
Elsevier |
series |
Molecular Therapy: Methods & Clinical Development |
issn |
2329-0501 |
publishDate |
2016-01-01 |
description |
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 situ 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. |
url |
http://www.sciencedirect.com/science/article/pii/S2329050117300402 |
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