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Ann Thorac Surg 1997;63:1527-1528
© 1997 The Society of Thoracic Surgeons
Division of Cardiothoracic Surgery, Department of Surgery, and Division of Pulmonary and Critical Care, Department of Medicine and the Thoracic Oncology Research Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
The articles in this issue by Takeda and associates [1] and Boasquevisque and colleagues [2] focus on gene therapy, a topic that is relatively new to thoracic surgeons, but that likely will play a significant role in the future management of diseases of the chest. Using gene transfer to address problems encountered in lung transplantation is of particular interest because most of the work to date has targeted either inherited diseases such as cystic fibrosis, where the gene abnormality has been identified and the strategy is to replace the abnormal gene with the wild type (normal) gene, or malignant disease, where either gene replacement or introduction of novel genes has been attempted. These two articles present an interesting contrast in the use of gene transfer technology. One uses the power of this approach to create a model of human disease, whereas the other clearly is aimed at specific therapeutic interventions.
See also 1556 and 1562.
Gene transfer in intact organs proves to be feasible, and it remains for investigators to harness the true power and capabilities of this technology. The leap between observations in an animal model and clinical applications remains considerable, despite the fact that clinical trials of gene therapy are in progress. Both Takeda and associates [1] and Boasquevisque and colleagues [2] note the very low efficiency of gene transfer in their experimental models. Issues of gene delivery and optimization of efficiency remain the biggest stumbling blocks to successful clinical application. Each of these studies employs a different method for gene delivery, and the fact remains that no ideal system is available even though considerable resources are being spent in an effort to define such a system. Viral vectors, such as employed by Boasquevisque and colleagues, can be modified to render them less immunogenic, which should serve to prolong transgene expression. Liposome-mediated delivery of plasmid DNA, as detailed by Takeda and associates, represents another potential technique capable of modification as has been done using the inactivated hemagglutinating virus of Japan (HJV).
The development of an experimental model of obliterative bronchiolitis using an endothelin-1 construct represents an advance in our understanding of the pathogenesis of obliterative bronchiolitis and provides a reproducible model available for further study, an intriguing and novel use of gene transfer technology. Although overexpression of endothelin-1 in this model seems to result in a pathologic picture that looks like clinical obliterative bronchiolitis, we cannot directly implicate endothelin-1 in human cases of obliterative bronchiolitis, as Takeda and associates point out, although increased level of endothelin-1 have been seen clinically. Obliterative bronchiolitis remains poorly understood, and only recently have there been any advances in developing an animal model that resembles the human disease. This article describes a system that appears to mimic some of the pathologic changes seen in clinical obliterative bronchiolitis, which may be used to study the interactions of growth factors or other therapeutic approaches. Armed with further knowledge regarding mechanism should allow for more precise targeting of therapeutic strategies. The HJV-liposome-mediated gene transfer method also deserves further study, especially in tumor systems, because efficiency and persistence may be an improvement over viral vectors.
One is tempted to look at the lovely transplant model of Boasquevisque and colleagues showing gene transfer with a marker construct and come to the conclusion that we are well on our way to clinical use. We have a long way to go before such a possibility is a reality, but we are moving in the right direction. Chapelier and associates [3] looked at a pig model of ex vivo adenovirus-mediated gene transfer and noted findings similar to the present study. They also found low levels (<1%) of gene expression, which could be improved with a longer duration of adenovirus incubation within the graft. The low efficiency of gene transfer also may be partially explained by the low temperature. The multiplicity of infection (number of viral particles/cell) also seems to be a determinant of efficiency of gene transfer [4], and Boasquevisque and colleagues have not provided us with an estimate of multiplicity of infection used in their model. Adenoviral attachment and uptake are separate but cooperative events, and whereas attachment may be unaffected by the low temperature, uptake may be more dependent on higher temperatures [5]. Protein expression within the cell likely is more sensitive to temperature, and the time course for protein production may be significantly lengthened by the cooler temperatures required for optimal organ preservation. In the current study, gene expression was poorer at 4°C than at 10°C. Perhaps looking at messenger RNA expression might be a better way to assess gene transfer in the transplant model than simply using the development of a marker gene.
Boasquevisque and colleagues [2] did not evaluate gene expression in other tissues with the exception of the native opposite lung, assuming that gene expression would be specific to the transplanted lung after ex vivo gene transfer in harvested lung isografts. Chapelier and associates [3] noted ß-galactosidase DNA and lacZ messenger RNA in heart, liver, skeletal muscle, spleen, and gonads of the ex vivo pig model. This finding of adenoviral dissemination in other organs, despite ex vivo gene transfer, will have to be addressed carefully before proceeding to human trials where intravascular injections of vector are used. The issue of the immune response to the adenoviral vector and transgene has not been well studied as yet in the transplant model and must be further defined.
Our own experience in bringing observations from an animal model to clinical trial is illustrative. We demonstrated efficacy in a preclinical model of malignant mesothelioma, which prompted us to bring this to clinical trial [6]. Using a recombinant viral vector requires that a number of regulatory steps be satisfied. Approval by the Food and Drug Administration was obtained only after we completed an exhaustive series of toxicity studies in rodents and subhuman primates. Clinical grade virus had to be made in sufficient titer and the viral production lot had to be certified free of replication-competent adenovirus. We were aided greatly by having the infrastructure of the University of Pennsylvania Institute for Human Gene Therapy available to us, and the time from laboratory to clinical trial still was 3.5 years. In a study of 15 patients we were able to demonstrate the feasibility and safety of adenovirus administration into the pleural space of patients with malignant mesothelioma and show convincing evidence of gene transfer (Treat J, Sterman DH, Litzky LA, et al; unpublished results). However, much work remains before this approach is likely to be therapeutically useful.
The pace from the laboratory to the patient is, by necessity, a slow one. The authors of the two articles in this issue of The Annals are to be congratulated for their efforts in extending our knowledge of gene transfer technology into new areas. We look forward to hearing repeatedly from both groups as their efforts move forward.
Footnotes
Address reprint requests to Dr Kaiser, Division of Cardiothoracic Surgery, Hospital of the University of Pennsylvania, 3400 Spruce St, 4 Silverstein, Philadelphia, PA 19104.
References
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  T. Tagawa, S. Dharmarajan, M. Hayama, T. Ishiyama, T. Suda, H. Itano, and G. A. Patterson Endobronchial Gene Transfer of Soluble Type I Interleukin-1 Receptor Ameliorates Lung Graft Ischemia-Reperfusion Injury Ann. Thorac. Surg., December 1, 2004; 78(6): 1932 - 1939. [Abstract] [Full Text] [PDF]
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 T. Tagawa, B. D. Kozower, S. A. Kanaan, N. Daddi, T. Suda, T. Oka, and G. A. Patterson Tumor necrosis factor inhibitor gene transfer ameliorates lung graft ischemia-reperfusion injury J. Thorac. Cardiovasc. Surg., October 1, 2003; 126(4): 1147 - 1154. [Abstract] [Full Text] [PDF]
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