Gene therapy in the 21st century.

Abstract

GENE THERAPY in the new century has begun in the face of both tragic and encouraging news. Since the death of an 18-year-old man on September 17, 1999 after injection of an adenoviral vector intended to correct his ornithine transcarbamylase deficiency, clinical gene therapy in general and adenoviral vectors in particular have received an unprecedented barrage of bad publicity. This painful experience provided some hard lessons for the advancement of gene therapy. The first lesson is that a gene therapy program should be scrutinized to ensure that the system is open and clear in all aspects from the manufacture of vectors and preparation of a protocol to monitoring and evaluation of clinical trial. The second lesson is that gene therapy researchers should make every possible effort to educate the general public and the press regarding what we do and why we do it. Current gene therapy is regarded as translational research, it is at a point between the bench and the bedside. We must go back to the bench after reviewing the clinical data obtained from early phase trials in order to establish more effective and reliable strategies for the future. The completion of human genome sequencing is excellent news in the field of gene therapy. It is evident that we will soon identify a number of new potential target genes based on this spectacular project. Successful application in SCID-X1 patients (Science 288:669–672, 2000) and hemophilia patients (Nature Genetics 24:257–261, 2000) was very encouraging for gene therapy scientists. Of great importance is the variety of gene therapy protocols for advanced localized tumors including urogenital malignancies that have been conducted, demonstrating its feasibility and safety. The Japanese Society for Urological Gene Therapy was founded in 1999 in order to stimulate our communication and collaboration with other physicians and basic scientists. There is an urgent and increasing need for our urologists to have an understanding of the basic concepts of gene therapy, its potential applications, and its shortcomings. The second meeting of the Society was held on November 18th, 2000 in Okayama, Japan; a guest speaker, Prof. Kaneda, Professor and Chairman of the Gene Therapy Science Division, Graduate School of Medicine, Osaka University, and 15 active urologists reported the current status and future prospects of their gene therapy approaches. Among them, eight articles were selected for the publication of this issue including Dr. Kaneda’s special article. Dr. Kaneda originally developed HVJ (Hemagglutinating Virus of Japan; Sendai virus)-liposomes that are efficient in vitro and in vivo as gene delivery vehicles using fusion-mediated gene delivery. And further studies have resulted in the creation of HVJ-cationic liposomes with increased transfection efficiency. He has discussed the improvement of gene therapy technology with regard to his current research outcomes. Developed by Dr. Kaneda and his colleagues, the first clinical protocol for arteriosclerosis obliterans using hepatocyte growth factor is now in the final stage of review process by the Japanese National Committee for gene therapy. With regard to cancer gene therapy, one of the most promising approaches to restore programmed cell death in tumor cells is replacement of the p53 gene. Wada et al. and Irie et al., respectively, showed the efficacy of p53 gene therapy for bladder cancer. Antisense oligonucleotides targeted at the open reading frame of the bcl-2 mRNA cause a specific down-regulation of bcl-2 expression which leads to increased apoptosis. Uchida et al. reported the effects of antisense BCL-2 strategy in the treatment of renal cell cancer. As a novel molecular target for antisense strategy, Miyagi et al. highlighted 150-kDa oxygen regulated protein (ORP150), a new member of the heat shock protein family, in the treatment of prostate cancer. As a new gene therapy system, Yoshimura et al. introduced the Cre-LoxP system in detail and discussed the possible application to urogenital cancer gene therapy. Gene therapy for noncancerous disease was also discussed in this issue. Okui et al. introduced a new, innovative gene therapy system against viral infection termed the virion-target-viral-inactivation system. The system can be applied to many viral infections including HIV infection. Yokoyama et al. reviewed the recent advances in gene therapy and tissue engineering for urological dysfunction by introducing their original and intensive research. Therapeutic applications of myoblast transplantation and the growth factors including nerve growth factor (NGF) were also discussed. In conclusion, it is clear that gene therapy remains in its infancy since most clinical studies demonstrate no significant clinical response. Nevertheless, we already have sufficient evidence to believe that gene therapy will revolutionize the practice of medicine with the enormous increase in functional genes