Crisis of adenoviruses in human gene therapy

Abstract

Michael McCarthy (March 18, p 997)1McCarthy M US FDA rejects defence of gene therapy trial.Lancet. 2000; 355: 997Google Scholar reports that the US Food and Drug Administration (FDA) rejects arguments made by the University of Pennsylvania in defence of its genetherapy programme, within which a patient aged 18 years with ornithine-cytosine transferase (OCT) deficiency died last autumn. After an investigation of the event, the FDA stopped the trials and others being done at the University's Institutes for Human Gene Therapy. In these trials, replication-defective adenoviruses (Ad) were used as vectors for delivering therapeutic genes to target tissues. Although so-called first generation Ad vectors, which are E1a/E1b gene deleted, are theoretically non-replicative, they could exhibit some residual gene expression, resulting in untoward vector-related side-effects.2Teramoto S Matsuse T Marsui H et al.Recombinant E1-deleted adenovirus vector induces apoptosis in two lung cancer cell lines.Eur Respir J. 1999; 13: 1125-1132Crossref PubMed Scopus (15) Google Scholar, 3Boucher RC Status of gene therapy for cystic fibrosis lung disease.J Clin Invest. 1999; 103: 441-445Crossref PubMed Scopus (126) Google Scholar, 4Welsh MJ Gene transfer for cystic fibrosis.J Clin Invest. 1999; 103: 1165-1166Crossref Scopus (40) Google Scholar In the patient who developed OCT after Admediated gene transfer, the administered titre of Ad vector (1011 plaque forming unit [pfu]/kg) was very high. It is about equal to 1014 viral particles per body. It is not hard to assume that such a high number of Ad vectors must contain very high numbers of non-viable vector particles, which could induce serious untoward effects on the patient. Although the Ad-mediated gene transduction was found in bone, spleen, and other organs of the patient, this is not only because of the vector's quality, but also because of the hepatic insufficiency of the background disease. Because more than 90% of Ad vectors administered intravenously are taken up by the liver in rodents and human beings, the systemic spread of Ad vectors is very unusual in individuals with normal liver function. Thus, two consequences could be envisioned. First, vectors' quality should be improved in terms of purifying the viable viral particles to minimise the toxicity vector protein. Inversely, target-cell-specific expression of Ad vectors is necessary to reduce the toxicity of viral vectors. Second, the patients enrolled onto the gene-therapy trials should be more carefully selected when the vector is administered intravenously. Although the death of the patient is the worst outcome in the history of human gene therapy, and is tragic, the cessation of all gene therapy trials using Ad vectors in human beings is an over reaction. At the gene-therapy workshop of annual conference of Japanese Respiratory Society, Hiroshima, Japan, March 23–24, the future of Ad-mediated gene therapy was discussed. In Japan, preclinical gene-therapy trials are now underway to test for the efficacy and safety of first-generation Ad vectors in patients with lung carcinoma. Obviously, the patients' responses to Ad vectors differ, depending on the route of administration of the vector. Although the systemic shedding of Ad vectors was detected in our trials in Japan, no serious untoward effects were found in first six patients. In the USA, clinical trials using Ad vectors have been done on over 180 patients with cystic fibrosis, without serious toxicity.3Boucher RC Status of gene therapy for cystic fibrosis lung disease.J Clin Invest. 1999; 103: 441-445Crossref PubMed Scopus (126) Google Scholar, 4Welsh MJ Gene transfer for cystic fibrosis.J Clin Invest. 1999; 103: 1165-1166Crossref Scopus (40) Google Scholar These observations suggest that the airway route of administration of Ad vectors is much safer than intravenous administration of Ad vectors in human beings. In addition, host immune and inflammatory responses caused by Ad vectors varies in different cells, organs, and individuals. It is true that further applications of current Ad vectors in gene therapy in vivo will require modification to improve efficiency and minimise the toxic and inflammatory responses in patients with lung disease.5Collins FS Medical and societal consequences of the human genome projects.N Engl J Med. 1999; 341: 28-37Crossref PubMed Scopus (629) Google Scholar However, gene, therapy trials using Ad vectors should carry on, provided the patients and volunteers are well selected, since the improvement of efficiency of gene transfer of vectors might solve the safety issue of Ad vectors in terms of the ratio of particle numbers per pfu.