Gene transfer to cerebral blood vessels after subarachnoid hemorrhage

Vasospasm remains a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage. One step toward gene therapy to prevent spasm of cerebral vessels is to determine whether subarachnoid blood prevents transgene expression.

Vasospasm was induced in mongrel dogs using the double-hemorrhage intracranial-injection model. Diameter of the basilar artery was assessed by angiography, and profound vasospasm (> 50% decrease in diameter) was demonstrated at 4 and 7 days. Recombinant adenovirus expressing nuclear-targeted beta-galactosidase (reporter gene) under the control of the cytomegalovirus promoter was injected into the cisterna magna at the same time as (n = 9) or 2 days after (n = 4) injection of blood for induction of vasospasm. Brains were removed and examined histochemically for expression of nuclear beta-galactosidase.

At 2 to 7 days, beta-galactosidase was expressed in leptomeninges over the brain stem, cortex, cerebral arteries, in small vessels in the cerebrum and brain stem, and in the ependymal lining of the ventricles. Transgene expression was observed in adventitia of blood vessels but not in vascular muscle or endothelium. Transgene expression was observed after simultaneous injection of virus and blood or when virus was injected 2 days after blood.

The findings indicate that intracisternal injection of recombinant adenovirus can be used for gene transfer to cerebral blood vessels 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 vessels and perivascular tissues may be useful for prevention or treatment of cerebral vasospasm after subarachnoid hemorrhage.