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Neurosurgery. 1997 Apr;40(4):789-803; discussion 803-4.

Cellular and molecular neurosurgery: pathways from concept to reality--part I: target disorders and concept approaches to gene therapy of the central nervous system.

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Department of Neurological Surgery, Childrens Hospital Los Angeles, University of Southern California School of Medicine, USA.


Recent advances in cellular and molecular biology and better understanding of genetic and biochemical bases of different central nervous system (CNS) disorders have made gene therapy of the CNS a realistic goal. Concept approaches for gene therapy of CNS disorders are reviewed and include the following: 1) gene replacement with a single normal allele to correct the inherited global neurodegenerative disorders, such as enzyme deficiencies; 2) brain repair to restore the function of a particular subset of cells that were lost because of a neurodegenerative process; 3) gene therapy of brain tumors; and 4) gene therapy of stroke. Techniques of viral vector-mediated CNS transfer of a therapeutic gene, transplantation of genetically modified cells, fetal embryonic implantation and/or implantation of genetically engineered neural progenitor cells, and production of a specific enzyme, neurotransmitter, and/or growth factor are discussed with respect to the therapeutic potential for global and localized CNS neurodegenerative disorders and stroke. 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 monoclonal antibody gene transfer, are briefly discussed. In addition to summarizing 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 cellular expression of the transgene, and the negatives associated with the concepts of gene therapy, such as transient gene expression, toxicity of viral proteins, drawbacks of antisense therapy, and the problem of immune response to the transfected protein, have been also identified.

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