Self-complementary adeno-associated virus serotype 2 vector: global distribution and broad dispersion of AAV-mediated transgene expression in mouse brain

The blood–brain barrier is the main obstacle to efficient delivery of therapeutic reagents, including viral vectors, into the central nervous system (CNS) for treating global CNS diseases. In this study, the effects of mannitol infusions on global brain gene expression of a novel AAV vector were exa...

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Bibliographic Details
Published in:Molecular therapy 2003-12, Vol.8 (6), p.911-917
Main Authors: Fu, Haiyan, Muenzer, Joseph, Samulski, Richard J, Breese, George, Sifford, Jerillyn, Zeng, Xinhua, McCarty, Douglas M
Format: Article
Language:English
Subjects:
Animals
Brain
Brain - drug effects
Brain - metabolism
Dependovirus
Diuretics, Osmotic - pharmacology
Gene expression
Gene therapy
Genes, Reporter
Genetic Therapy
Genetic Vectors
Genomes
Mannitol - pharmacology
Mice
Nervous system
Organ Specificity
Reagents
Spinal cord
Transduction, Genetic
Transgenes - drug effects
Vectors (Biology)
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Summary:The blood–brain barrier is the main obstacle to efficient delivery of therapeutic reagents, including viral vectors, into the central nervous system (CNS) for treating global CNS diseases. In this study, the effects of mannitol infusions on global brain gene expression of a novel AAV vector were examined after intravenous (iv) or intracisternal injection. Initially, a self-complementary adeno-associated virus serotype 2 vector (scAAV) was compared to traditional single-stranded AAV2 vector for reporter gene expression in the brain of adult mice with or without pretreatment of an iv mannitol infusion. One to two months postinjection, analysis of vector-transduced green fluorescent protein (GFP) expression in the brain revealed that vector delivery to the CNS via iv injection required pretreatment with mannitol. This expression was observed only when scAAV vectors were used. Using these conditions, transgene expression was observed in various neurons and glial cells throughout the brain. The peripherally administered scAAV vectors also transduced the cells in multiple somatic tissues with efficient expression in liver (20–30% of hepatocytes), but was less efficient in other somatic tissues. Intracisternal injection of scAAV vector produced a broad and intense transgene expression in both neurons and glial cells in the CNS of injected mice ranging from the olfactory area to the brain stem and spinal cord. More than 50% of the Purkinje cells in the cerebellum expressed GFP. Intravenous infusion of mannitol before intracisternal injection of the scAAV vector enhanced the dispersion of the vector in the CNS. Further optimization of these steps combining peripheral and intracisternal scAAV gene delivery should facilitate the development of treatments for global CNS diseases, especially diseases involving both the somatic system and the CNS, such as lysosomal storage disorders.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2003.08.021