Developers
Nicole K Polinski, Fredric P Manfredsson, Katrina L Paumier, Caryl E Sortwell, etc.
Description of the technology
The technology develops new original approach to the treatment of age-associated and degenerative diseases. 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. Results demonstrate that aging is a critical covariate to consider when designing gene therapy approaches for PD.
Practical application
The effects of vector rAAV9, which are underlies this technology, such as an elicitation of an adaptive immune response and subsequent neuronal loss that has been associated with this vector when delivering potentially antigenic proteins, can be used for creation of new gene-therapeutic approaches for treatment of age-associated diseases.
The ability of rAAV9 to cross the blood-brain barrier and possibly escape the brain tissues after intra-parenchymal injection may also be an important consideration. It is possible, that altering the promoter, transgene, vector backbone, or titer may targetedly change these parameters and improve the safety profile of the rAAV9 for use in gene therapy for neurodegenerative diseases.
The impact of age on viral vector transduction efficiency is an extremely important consideration, because efficient transduction will be required for functionally-meaningful gene therapy for age-related neurodegenerative diseases.
Laboratories
- Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, (USA)
- Neuroscience Graduate Program, Michigan State University, East Lansing, (USA)
- Mercy Health Saint Mary’s, Grand Rapids, (USA)
Links
http://www.nature.com/articles/mtm201682
Publications
- Polinski, N.K. et al. «Impact of age and vector construct on striatal and nigral transgene expression." 3 Mol Ther Methods Clin Dev. (2016): 16082.
- Polinski, N.K. et al. «Recombinant adenoassociated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain." 36 Neurobiol Aging, (2015): 1110–1120.
- Collier, T.J. et al. «Interrogating the aged striatum: robust survival of grafted dopamine neurons in aging rats produces inferior behavioral recovery and evidence of impaired integration." 77 Neurobiol Dis, (2015): 191–203.