CELLULAR AND MOLECULAR NEUROSURGERY - PATHWAYS FROM CONCEPT TO REALITY .2. VECTOR SYSTEMS AND DELIVERY METHODOLOGIES FOR GENE-THERAPY OF THE CENTRAL-NERVOUS-SYSTEM

DIFFERENT VECTOR SYSTEMS that have been used and/or specifically devel oped for central nervous system (CNS) gene transfer studies are briefl y discussed along with their advantages and disadvantages with respect to potential clinical application. These include retroviruses, recomb inant herpes simplex virus, adenoviruses, adenoassociated viruses, enc apsulation of plasmid deoxyribonucleic acid into cationic liposomes, a nd neural and oliogodendroglial stem cells. Particular attention has b een paid to relate the modality of a specific CNS gene therapy to the strategy for adequate delivery of genetic material to the brain for ei ther global or localized CNS neurodegenerative chronic disorder, as we ll as for CNS tumors and stroke. Techniques to circumvent the ''imperm eable'' blood-brain barrier and how to breach the more versatile blood -brain-tumor barrier to deliver the genetic material to the target CNS cells are reviewed and include the following: 1) local stereotactic ( CNS injection/infusion of viral vectors, administration of vector prod ucer cells, or cell replacement; 2) local administration of genetic ma terial into the cerebrospinal fluid ventriculocisternal system; 3) osm otic opening of the blood-brain barrier; 4) local intra-arterial infus ion; and 5) administration of blood-brain-tumor barrier permeabilizers , such as a bradykinin B2 agonist RMP-7. It is concluded that gene the rapy for several brain disorders holds great potential, as suggested m ainly by in vitro experiments and, to some extent, by a limited number of animal experiments. However, several drawbacks currently hamper th e application of gene therapy under the clinical setting. The problems associated with gene therapy that still present major obstacles are a s follows: 1) inefficient transfection of host cells by viral vectors; 2) restricted delivery of genetic material across vascular barriers o f the CNS and brain tumors; 3) nonselective expression of the transgen e; and 4) in situ CNS regulation of the transgene expression in a ther apeutically controlled manner, as imposed by the course and phenotype of the CNS disease.