Recent advances in the application of gene therapy to human disease.

PURPOSE: To review the recent advances in the application of genetic modification strategies to the therapy of human diseases for which a molecular defect is known.
METHODS: A computerized data bank search, the minutes of the National Institutes of Health (NIH) Recombinant DNA Advisory Committee published in the Federal Record, and reports of human clinical trials were used as data sources for this review. Clinical trials included in this review were published in the literature or approved by the NIH Recombinant DNA Advisory Committee. STUDY SELECTION: Evaluations of the efficacy of genetic modification strategies in clinical trials in human and in animal models are summarized. The design and outcome of the genetic modification strategies employed are reviewed for 16 marking trials, 16 gene replacement trials for molecular deficiency diseases, 3 chemoprotection and 4 chemotherapy sensitization trials, 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 marrow can contribute to relapse following autologous bone marrow transplants. The use of genetic modification for the replacement of missing or deficient genes in severe combined immunodeficiency, familial hypercholesterolemia, and cystic fibrosis has been associated with encouraging results so far. Clinical genetic therapy trials involving cancer vaccines, antisense oligonucleotides, adoptive immunotherapy with genetically modified T cells, delivery vectors containing interleukin-1 receptor inhibitor for arthritis, replacement strategies for storage diseases, and genetic suppression of human immunodeficiency viral replication are just commencing.
CONCLUSIONS: The clinical application of genetic modification techniques has thus far been successful in the beginning 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 clinical trials in the future may be based on the analysis of assays for short-term surrogate endpoints, as well as on the therapeutic outcomes of the trial, such as survival or remission.