GENE-TRANSFER TO CEREBRAL BLOOD-VESSELS AFTER SUBARACHNOID HEMORRHAGE

Background and Purpose Vasospasm remains a major cause of morbidity an d mortality after aneurysmal subarachnoid hemorrhage. One step toward gene therapy to prevent spasm of cerebral vessels is to determine whet her subarachnoid blood prevents transgene expression. Methods Vasospas m was induced in mongrel dogs using the double-hemorrhage intracranial -injection model. Diameter of the basilar artery was assessed by angio graphy, and profound vasospasm (>50% decrease in diameter) was demonst rated at 4 and 7 days. Recombinant adenovirus expressing nuclear-targe ted beta-galactosidase (reporter gene) under the control of the cytome galovirus promoter was injected into the cisterna magna at the same ti me as (n=9) or 2 days after (n=4) injection of blood for induction of vasospasm. Brains were removed and examined histochemically for expres sion of nuclear beta-galactosidase. Results At 2 to 7 days, beta-galac tosidase was expressed in leptomeninges over the brain stem, cortex, c erebral arteries, in small vessels in the cerebrum and brain stem, and in the ependymal lining of the ventricles. Transgene expression was o bserved in adventitia of blood vessels but not in vascular muscle or e ndothelium. Transgene expression was observed after simultaneous injec tion of virus and blood or when virus was injected 2 days after blood, Conclusions The findings indicate that intracisternal injection of re combinant adenovirus can be used for gene transfer to cerebral blood v essels and overlying meninges, even in the presence of cisternal blood . We speculate that transfer of genes using recombinant viral vectors that encode for enzymes with vasodilator function to cerebral blood ve ssels and perivascular tissues may be useful for prevention or treatme nt of cerebral vasospasm after subarachnoid hemorrhagic.