Adenovirus-mediated gene transfer in vivo to cerebral blood vessels and perivascular tissue in mice

Abstract

Background and purpose: Gene transfer to cerebral blood vessels has been accomplished in rats and dogs by injection of replication-deficient adenovirus into cerebrospinal fluid. In this study we examined transgene expression after injection of adenovirus into the cerebrospinal fluid of mice. Responses were observed in ICR mice and C57BL/6 mice, which are outbred and inbred strains, respectively.

Methods: We injected replication-deficient recombinant adenovirus expressing nuclear targeted beta-galactosidase, driven by either the Rous sarcoma virus promoter (AdRSV-betaGal) or the cytomegalovirus promoter (AdCMV-betaGal), into the cisterna magna of anesthetized ICR and C57BL/6 strains of mice. The brains were examined from 1 to 21 days after injection by chemiluminescent enzyme activity assay or histochemical staining.

Results: After injection of AdRSV-betaGal, expression of beta-galactosidase in ICR mice peaked on day 7 and returned to basal by day 14. Expression of beta-galactosidase in C57BL/6 mice was maximal on days 7 to 14 and was minimal by day 21 after injection of AdRSV-betaGal. After injection of AdCMV-betaGal in C57BL/6 mice, peak expression of transgene occurred on day 1 and was greatly diminished by day 3. Transgene expression was observed primarily on the ventral surface of the brain, with preferential expression in leptomeninges and adventitia along the major cerebral arteries of that region.

Conclusions: Injection of recombinant adenovirus in the cisterna magna resulted in transgene expression in leptomeninges and perivascular tissue of cerebral blood vessels in two strains of mice. The CMV promoter elicited rapid but short-lived expression of the transgene, while the RSV promoter elicited slower, more sustained transgene expression. Expression of AdRSV transgene was prolonged in C57BL/6 mice compared with ICR mice. This approach for gene transfer may be useful to study cerebral vascular biology in genetically altered strains of mice.