Gene expression from recombinant viral vectors in the central nervous system after blood-brain barrier disruption.
Direct intracerebral injection of recombinant adenoviral vectors within the brain parenchyma or the ventricular system results in a limited volume of distribution of virus, as demonstrated by transgene expression. Global delivery to the central nervous system may increase the use of these vectors but only if the viral vectors can cross the blood-brain barrier and result in transduction of the underlying cells. This short-term study examines whether osmotic disruption with mannitol can result in sufficient opening of the vascular endothelium to allow for passage of replication-defective adenovirus containing the Escherichia coli beta-galactosidase gene (lacZ). Virus was injected into the carotid artery of rats after blood-brain barrier disruption with intracarotid hypertonic mannitol, and the animals were killed and analyzed after 4 days. Histochemical analysis and electron microscopy confirmed expression of the E. coli lacZ gene in the pericapillary astrocytes of the ipsilateral cerebral cortex and deep grey matter. Furthermore, the extent of gene transfer and expression correlated with the degree of barrier opening, as measured by Evans blue staining. Transgene expression was not seen in control animals that received intracarotid saline before recombinant virus injection. These data demonstrate, for the first time, that blood-brain barrier disruption can allow for the delivery of functional viral vectors to the central nervous system.
Doran
S E
SE
Department of Surgery, University of Michigan Medical Center, Ann Arbor, USA.
Ren
X D
XD
Betz
A L
AL
Pagel
M A
MA
Neuwelt
E A
EA
Roessler
B J
BJ
Davidson
B L
BL
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000502:physiology* / Q000648:ultrastructure; D004926:Escherichia coli / Q000235:genetics; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007763:Lac Operon; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley; D011995:Recombination, Genetic; D001616:beta-Galactosidase / Q000378:metabolism
D008353:Mannitol; D001616:beta-Galactosidase