Effect of adeno-associated virus serotype and genomic structure on liver transduction and biodistribution in mice of both genders
Pañeda A (1), Vanrell L (1), Mauleon I (1), Crettaz JS (1), Berraondo P (1), Timmermans EJ (2), Beattie SG (2), Twisk J (2), van Deventer S (2), Prieto J (1,3), Fontanellas A (1), Rodriguez-Pena MS (2), Gonzalez-Aseguinolaza G. (1)
(1) Division Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
(2) AMT BV, 1105 BA Amsterdam, The Netherlands.
(3) Liver Unit, University Clinic, University of Navarra, 31008 Pamplona, Spain.
Recombinant adeno-associated viral (AAV) vectors have unique properties, which make them suitable vectors for gene transfer. Here we assess the liver transduction efficiency and biodistribution of AAV-pseudotyped capsids (serotypes) 1, 5, 6, and 8, combined with single-stranded and double-stranded genomic AAV2 structures carrying the luciferase reporter gene after systemic administration. The analysis was performed in vivo and ex vivo, in male and female mice. Gender-related differences in AAV-mediated transduction and biodistribution were shown for the four serotypes.
Our data confirm the superiority of AAV8 over the rest of the serotypes, as well as a significant advantage of double-stranded genomes in terms of liver transduction efficiency, particularly in females. Regarding biodistribution, AAV5 displayed a narrower tropism than the other serotypes tested, transducing, almost exclusively, the liver. Interestingly, AAV1 and AAV8, in particular those having single-stranded genomes, showed high transduction efficiency of female gonads. However, no inadvertent germ line transmission of AAV genomes was observed after breeding single-stranded AAV8-injected female mice with untreated males.
In conclusion, double-stranded AAV8 vectors led to the highest levels of liver transduction in mice, as demonstrated by luciferase expression. Nevertheless, the transduction of other organs with AAV8 vectors could favor the use of less efficient serotypes, such as AAV5, which display a narrow tropism.
CITATION Hum Gene Ther. 2009 Aug;20(8):908-17