Recombinant adeno-associated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain

• Published in: Neurobiology of aging Vol. 36; no. 2; pp. 1110 - 1120
• Main Authors: Polinski, Nicole K., Gombash, Sara E., Manfredsson, Fredric P., Lipton, Jack W., Kemp, Christopher J., Cole-Strauss, Allyson, Kanaan, Nicholas M., Steece-Collier, Kathy, Kuhn, Nathan C., Wohlgenant, Susan L., Sortwell, Caryl E.
• Format: Journal Article
• Language: English
• Published: 13.10.2014
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2014.07.047

Clinical trials are examining the efficacy of viral vector-mediated gene delivery for treating Parkinson’s disease (PD). While viral vector strategies have been successful in preclinical studies, to date clinical trials have disappointed. This may be due to the fact that preclinical studies fail to account for aging. Aging is the single greatest risk factor for developing PD and age alters cellular processes utilized by viral vectors. We hypothesized that the aged brain would be relatively resistant to transduction when compared to 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 (SN) aged rats displayed 40-60% less GFP protein in the striatum, regardless of rat strain or duration of expression. Further, aged rats exhibited 40% fewer cells expressing GFP and 4-fold less GFP mRNA. rAAV2/5-mediated gene transfer is compromised in the aged rat midbrain, with deficiencies in early steps of transduction leading to significantly less mRNA and protein expression.