Enhanced CNS transduction from AAV.PHP.eB infusion into the cisterna magna of older adult rats compared to AAV9

Authors

Diptaman Chatterjee, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
David J. Marmion, Parkinson's Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA.
Jodi L. McBride, Divison of Neuroscience, Oregon National Primate Research Center, Beaverton; Departments of Behavioral Neuroscience and Neurology, Oregon Health and Science University, Portland, OR, USA.
Fredric P. Manfredsson, Parkinson's Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA.Follow
David Butler, Neural Stem Cell Institute, Regenerative Research Foundation, Rensselaer; Department of Biomedical Sciences, University at Albany, Albany, NY, USA.
Anne Messer, Neural Stem Cell Institute, Regenerative Research Foundation, Rensselaer; Department of Biomedical Sciences, University at Albany, Albany, NY, USA.
Jeffrey H. Kordower, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. jeffrey.kordower@asu.edu.

Document Type

Article

Abstract

The development of high efficiency, central nervous system (CNS) targeting AAV-based gene therapies is necessary to address challenges in both pre-clinical and clinical investigations. The engineered capsids, AAV.PHP.B and AAV.PHP.eB, show vastly improved blood-brain barrier penetration compared to their parent serotype, AAV9, but with variable effect depending on animal system, strain, and delivery route. As most characterizations of AAV.PHP variants have been performed in mice, it is currently unknown whether AAV.PHP variants improve CNS targeting when delivered intrathecally in rats. We evaluated the comparative transduction efficiencies of equititer doses (6 × 10vg) of AAV.PHP.eB-CAG-GFP and AAV9-CAG-GFP when delivered into the cisterna magna of 6-9-month old rats. Using both quantitative and qualitative assessments, we observed consistently superior biodistribution of GFP+ cells and fibers in animals treated with AAV.PHP.eB compared to those treated with AAV9. Enhanced GFP signal was uniformly observed throughout rostrocaudal brain regions in AAV.PHP.eB-treated animals with matching GFP protein expression detected in the forebrain, midbrain, and cerebellum. Collectively, these data illustrate the benefit of intracisternal infusions of AAV.PHP.eB as an optimal system to distribute CNS gene therapies in preclinical investigations of rats, and may have important translational implications for the clinical CNS targeting.

Publication Date

3-22-2021

Publication Title

Gene therapy

E-ISSN

1476-5462

PubMed ID

33753910

Digital Object Identifier (DOI)

10.1038/s41434-021-00244-y

Recommended Citation

Chatterjee, Diptaman; Marmion, David J.; McBride, Jodi L.; Manfredsson, Fredric P.; Butler, David; Messer, Anne; and Kordower, Jeffrey H., "Enhanced CNS transduction from AAV.PHP.eB infusion into the cisterna magna of older adult rats compared to AAV9" (2021). Translational Neuroscience. 1416.
https://scholar.barrowneuro.org/neurobiology/1416