Edward A. Neuwelt

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.

Delivery of Therapeutic Genes to Brain and Intracerebral Tumors

Delivery is a major issue in the treatment of neurological disease and tumors affecting the central nervous system (CNS). Delivery of genetic material to target cells at the molecular level has been reviewed elsewhere (please see the preceding chapters for reviews of new vectors and toxic genes for tumor therapy). Here we will address the macroscopic problem of delivery of vectors to brain tumors.

Delivery of Chemotherapeutics Across the Blood–Brain Barrier

The blood-brain barrier (BBB) limits drug delivery to brain tumors. We utilize intraarterial infusion of hyperosmotic mannitol to reversibly open the BBB by shrinking endothelial cells and opening tight junctions between the cells. This approach transiently increases the delivery of chemotherapy, antibodies, and nanoparticles to brain. Our preclinical studies have optimized the BBB disruption (BBBD) technique and clinical studies have shown its safety and efficacy. The delivery of methotrexate-based chemotherapy in conjunction with BBBD provides excellent outcomes in primary central nervous system lymphoma (PCNSL) including stable or improved cognitive function in survivors a median of 12 years (range 2-26 years) after diagnosis. The addition of rituximab to chemotherapy with BBBD for PCNSL can be safely accomplished with excellent overall survival. Our translational studies of thiol agents to protect against platinum-induced toxicities led to the development of a two-compartment model in brain tumor patients. We showed that delayed high-dose sodium thiosulfate protects against carboplatin-induced hearing loss, providing the framework for large cooperative group trials of hearing chemoprotection. Neuroimaging studies have identified that ferumoxytol, an iron oxide nanoparticle blood pool agent, appears to be a superior contrast agent to accurately assess therapy-induced changes in brain tumor vasculature, in brain tumor response to therapy, and in differentiating central nervous system lesions with inflammatory components. This chapter reviews the breakthroughs, challenges, and future directions for BBBD.