CELLULAR AND MOLECULAR NEUROSURGERY - PATHWAYS FROM CONCEPT TO REALITY .1. TARGET DISORDERS AND CONCEPT APPROACHES TO GENE-THERAPY OF THE CENTRAL-NERVOUS-SYSTEM

RECENT ADVANCES IN cellular and molecular biology and better understan ding of genetic and biochemical bases of different central nervous sys tem (CNS) disorders have made gene therapy of the CNS a realistic goal . Concept approaches for gene therapy of CNS disorders are reviewed an d include the following: 1) gene replacement with a single normal alle le to correct the inherited global neurodegenerative disorders, such a s enzyme deficiencies; 2) brain repair to restore the function of a pa rticular subset of cells that were lost because of a neurodegenerative process; 3) gene therapy of brain tumors; and 4) gene therapy of stro ke. Techniques of viral vector-mediated CNS transfer of a therapeutic gene, transplantation of genetically modified cells, fetal embryonic i mplantation and/or implantation of genetically engineered neural proge nitor cells, and production of a specific enzyme, neurotransmitter, an d/or growth factor are discussed with respect to the therapeutic poten tial for global and localized CNS neurodegenerative disorders and stro ke. Transfection of the CNS tumor cells with the drug susceptibility ( ''suicide'') gene and/or ''toxic'' gene and antisense strategies and a concept of adoptive immunotherapy of brain tumors are also discussed. Other approaches, such as transfer of drug-resistant genes and monocl onal antibody gene transfer, are briefly discussed. In addition to sum marizing current principles of gene therapy for several groups of CNS disorders, the issues that remain to be resolved in clinical reality, such as delivery of the genetic material and regulation of the cellula r expression of the transgene, and the negatives associated with the c oncepts of gene therapy, such as transient gene expression, toxicity o f viral proteins, drawbacks of antisense therapy, and the problem of i mmune response to the transfected protein, have been also identified.