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Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12754-9. Epub 2001 Oct 9.

Brain-specific expression of an exogenous gene after i.v. administration.

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  • 1Department of Medicine, University of California School of Medicine, Los Angeles, CA 90024, USA.


The treatment of brain diseases with gene therapy requires the gene to be expressed throughout the central nervous system, and this is possible by using gene targeting technology that delivers the gene across the blood-brain barrier after i.v. administration of a nonviral formulation of the gene. The plasmid DNA is targeted to brain with pegylated immunoliposomes (PILs) using a targeting ligand such as a peptidomimetic mAb, which binds to a transporting receptor on the blood-brain barrier. The present studies adapt the PIL gene targeting technology to the mouse by using the rat 8D3 mAb to the mouse transferrin receptor. Tissue-specific expression in brain and peripheral organs of different exogenous genes (beta-galactosidase, luciferase) is examined at 1-3 days after i.v. injection in adult mice of the exogenous gene packaged in the interior of 8D3-PIL. The expression plasmid is driven either by a broadly expressed promoter, simian virus 40, or by a brain-specific promoter taken from the 5' flanking sequence of the human glial fibrillary acidic protein (GFAP) gene. The transgene is expressed in both brain and peripheral tissues when the simian virus 40 promoter is used, but the expression of the exogenous gene is confined to the brain when the transgene is under the influence of the brain-specific GFAP promoter. Confocal microscopy colocalizes immunoreactive bacterial beta-galactosidase with immunoreactive GFAP in brain astrocytes. These studies indicate that tissue-specific gene expression in brain is possible after the i.v. administration of a nonviral vector with the combined use of gene targeting technology and tissue-specific gene promoters.

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