RECENT ADVANCES IN THE APPLICATION OF GENE-THERAPY TO HUMAN-DISEASE

PURPOSE: To review the recent advances in the application of genetic m odification strategies to the therapy of human diseases for which a mo lecular defect is known. METHODS: A computerized data bank search, the minutes of the National Institutes of Health (NIH) Recombinant DNA Ad visory Committee published in the Federal Record, and reports of human clinical trials were used as data sources for this review. Clinical t rials included in this review were published in the literature or appr oved by the NIH Recombinant DNA Advisory Committee. STUDY SELECTION: E valuations Of the efficacy of genetic modification strategies in clini cal trials in human and in animal models are summarized. The design an d outcome of the genetic modification strategies employed are reviewed for 16 marking trials, 16 gene replacement trials for molecular defic iency diseases, 3 chemoprotection and 4 chemotherapy sensitization tri als, 11 cancer vaccine trials, 2 antisense oligonucleotide trials, and 3 molecular immunotherapy trials. DATA SYNTHESIS: The marking trials have shown that residual leukemia cells in the infused autologous marr ow can contribute to relapse following autologous bone marrow transpla nts. The use of genetic modification for the replacement of missing or deficient genes in severe combined immunodeficiency, familial hyperch olesterolemia, and cystic fibrosis has been associated with encouragin g results so far. Clinical genetic therapy trials involving cancer vac cines, antisense oligonucleotides, adoptive immunotherapy with genetic ally modified T cells, delivery vectors containing interleukin-l recep tor inhibitor for arthritis, replacement strategies for storage diseas es, and genetic suppression of human immunodeficiency viral replicatio n are just commencing. CONCLUSIONS: The clinical application of geneti c modification techniques has thus far been successful in the beginnin g phases of this field. These early results suggest that continuation of gene therapy trials designed to correct the molecular changes that lead to disease states in humans is warranted. Evaluation of such clin ical trials in the future may be based on the analysis of assays for s hort-term surrogate endpoints, as well as on the therapeutic outcomes of the trial, such as survival or remission.