title: Capsid serotype and timing of injection determines AAV transduction in the neonatal mice brain.
abstract: Adeno-associated virus (AAV) mediated gene expression is a powerful tool for gene therapy and preclinical studies. A comprehensive analysis of CNS cell type tropism, expression levels and biodistribution of different capsid serotypes has not yet been undertaken in neonatal rodents. Our previous studies show that intracerebroventricular injection with AAV2/1 on neonatal day P0 results in widespread CNS expression but the biodistribution is limited if injected beyond neonatal day P1. To extend these observations we explored the effect of timing of injection on tropism and biodistribution of six commonly used pseudotyped AAVs delivered in the cerebral ventricles of neonatal mice. We demonstrate that AAV2/8 and 2/9 resulted in the most widespread biodistribution in the brain. Most serotypes showed varying biodistribution depending on the day of injection. Injection on neonatal day P0 resulted in mostly neuronal transduction, whereas administration in later periods of development (24-84 hours postnatal) resulted in more non-neuronal transduction. AAV2/5 showed widespread transduction of astrocytes irrespective of the time of injection. None of the serotypes tested showed any microglial transduction. This study demonstrates that both capsid serotype and timing of injection influence the regional and cell-type distribution of AAV in neonatal rodents, and emphasizes the utility of pseudotyped AAV vectors for translational gene therapy paradigms.
authors.affiliation: Center for Translational Research in Neurodegenerative Disease and Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Paramita
authors.initials: P
authors.lastname: Chakrabarty
authors.forename: Awilda
authors.initials: A
authors.lastname: Rosario
authors.forename: Pedro
authors.initials: P
authors.lastname: Cruz
authors.forename: Zoe
authors.initials: Z
authors.lastname: Siemienski
authors.forename: Carolina
authors.initials: C
authors.lastname: Ceballos-Diaz
authors.forename: Keith
authors.initials: K
authors.lastname: Crosby
authors.forename: Karen
authors.initials: K
authors.lastname: Jansen
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
authors.forename: Ji-Yoen
authors.initials: JY
authors.lastname: Kim
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Jankowsky
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Yona
authors.initials: Y
authors.lastname: Levites
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000821:virology; D001921:Brain / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D002213:Capsid / Q000378:metabolism*; D000229:Dependovirus / Q000145:classification* / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D007267:Injections; D051379:Mice; D012703:Serotyping; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods*; D056189:Viral Tropism
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins