Recombinant Adeno-Associated Virus Type 2, 4, and 5 Vectors: Transduction of Variant Cell Types and Regions in the Mammalian Central Nervous System

Recombinant adeno-associated virus vectors based on serotype 2 (rAAV2) can direct transgene expression in the central nervous system (CNS), but it is not known how other rAAV serotypes perform as CNS gene transfer vectors. Serotypes 4 and 5 are distinct from rAAV2 and from each other in their capsid...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2000-03, Vol.97 (7), p.3428-3432
Main Authors: Davidson, Beverly L., Stein, Colleen S., Heth, Jason A., Martins, Ines, Kotin, Robert M., Derksen, Todd A., Zabner, Joseph, Ghodsi, Abdi, Chiorini, John A.
Format: Article
Language:English
Subjects:
adeno-associated virus
Animals
Astrocytes
beta-Galactosidase - genetics
Biological Sciences
Brain
Cell lines
Cells
Central nervous system
Central Nervous System - cytology
Central Nervous System - virology
Dependovirus - genetics
Gene therapy
Genetic Vectors
Immunohistochemistry
Male
Mammals
Mice
Mice, Inbred C57BL
Nervous system
Neuroglia
Neurons
Recombination, Genetic
Septum of brain
Transduction, Genetic
Transgenes
Viruses
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Summary:Recombinant adeno-associated virus vectors based on serotype 2 (rAAV2) can direct transgene expression in the central nervous system (CNS), but it is not known how other rAAV serotypes perform as CNS gene transfer vectors. Serotypes 4 and 5 are distinct from rAAV2 and from each other in their capsid regions, suggesting that they may direct binding and entry into different cell types. In this study, we examined the tropisms and transduction efficiencies of β -galactosidase-encoding vectors made from rAAV4 and rAAV5 compared with similarly designed rAAV2-based vectors. Injection of rAAV5 β -galactosidase (β gal) or rAAV4β gal into the lateral ventricle resulted in stable transduction of ependymal cells, with approximately 10-fold more positive cells than in mice injected with rAAV2β gal. Major differences between the three vectors were revealed upon striatal injections. Intrastriatal injection of rAAV4β gal resulted again in striking ependyma-specific expression of transgene, with a notable absence of transduced cells in the parenchyma. rAAV2β gal and rAAV5β gal intrastriatal injections led to β -gal-positive parenchymal cells, but, unlike rAAV2β gal, rAAV5β gal transduced both neurons and astrocytes. The number of transgene-positive cells in rAAV5β gal-injected brains was 130 and 5,000 times higher than in rAAV2β gal-injected brains at 3 and 15 wk, respectively. Moreover, transgene-positive cells were widely dispersed throughout the injected hemisphere in rAAV5β gal-transduced animals. Together, our data provide in vivo support for earlier in vitro work, suggesting that rAAV4 and rAAV5 gain cell entry by means of receptors distinct from rAAV2. These differences could be exploited to improve gene therapy for CNS disorders.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.050581197