CNS Transduction Benefits of AAV-PHP.eB over AAV9 Are Dependent on Administration Route and Mouse Strain

• Published in: Molecular therapy. Methods & clinical development Vol. 19; pp. 447 - 458
• Main Authors: Mathiesen, Sophie N., Lock, Jasmine L., Schoderboeck, Lucia, Abraham, Wickliffe C., Hughes, Stephanie M.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 11.12.2020; American Society of Gene & Cell Therapy; Elsevier
• Subjects: AAV; AAV-PHP.eB; AAV9; central nervous system; gene therapy; intravenous; Original; viral vector; intravenous; AAV; AAV-PHP.eB; gene therapy; viral vector; AAV9; central nervous system
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2020.10.011

Adeno-associated viral (AAV) vectors are attractive tools for central nervous system (CNS) gene therapy because some vectors can cross the blood-brain barrier (BBB), allowing them to be used as minimally invasive treatments. A novel AAV vector recently evolved in vivo, AAV-PHP.eB, has been reported to cross the BBB more effectively than the existing gold standard AAV9, but not under all conditions. Here, we compared the efficacy of single-stranded AAV-PHP.eB and AAV9 in targeting mouse CNS and peripheral tissues after administration via various routes, in two different mouse strains (C57BL/6J and B6C3), and after packaging AAV-PHP.eB with a self-complementary genome. We found that AAV-PHP.eB produced higher CNS transduction than AAV9 after intravenous injection, but only in C57BL/6J and not in B6C3 mice. AAV-PHP.eB and AAV9 produced similar CNS transduction when the administration route did not require the vectors to cross the BBB. Packaging AAV-PHP.eB with a self-complementary genome increased overall CNS transduction, but at the expense of strong neuronal tropism. AAV-PHP.eB resulted in less transduction of liver tissue than AAV9 under all conditions. Taken together, these results suggest the potential for AAV-PHP.eB as a vector for CNS gene therapy applications, but consideration will be required for translation beyond mouse models. [Display omitted] Engineered AAV vector AAV-PHP.eB has improved ability over AAV9 to transduce mouse CNS after intravenous administration. Using various methods of administration, we show this is due to the increased ability of AAV-PHP.eB to cross the blood-brain barrier; however, this is dependent on the mouse strain used.