Dr. Shaf Keshavjee
Program Medical Director, Surgical Services & Critical Care, UHN
Thoracic Surgery Research Laboratory: Lung Injury and Gene Therapy in Lung Transplantation
There are two major areas which limit the successful application of lung transplantation namely, ischemia reperfusion injury and bronchiolitis obliterans. Our work deals with the exploration of the underlying mechanisms of both of these injuries and the development of therapeutic strategies to prevent or reverse both of these.
We have developed a technique of lung preservation (LPD solution) that has lead to significant improvements in lung function after transplantation. This solution has now been translated into clinical use in our lung transplant program as well as in transplant programs around the world. We have explored several areas in ischemia reperfusion injury including the role of complement and cytokine related lung injury related to reperfusion. This work is done in cell culture models, rat single lung transplant models and pig single lung transplant models.
Our major project is gene therapy in lung transplantation. We are working on techniques to genetically modify the donor lung so that it is better able to deal with the stress imposed upon it by the transplantation process. We hope to address both ischemia reperfusion injury and obliterative bronchiolitis with gene therapeutic techniques.
To this end, we have shown that immunosuppression related to transplantation leads to augmented expression of the transgene. We have also shown that the immunosuppression leads to prolonged expression of transgene.
The immune response to the transfected adenoviral gene has been a major limitation and our work has demonstrated that gene therapy has a very high likelihood of success in the setting of transplantation were some of the limitations can be overcome by the immunosuppression.
In fact, we have also demonstrated that immunosuppression of transplantation can allow effective re-transfection of the recipient without a significant immune response. We have also shown that the optimal time of delivery of the gene of interest would be to the donor under conditions of norothermia, prior to extraction and cold storage of the organ for transportation and transplantation.
In addressing obliterative bronchiolitis in a rat tracheal transplant model of fibrous airway obliteration related to transplantation, we have shown that adenoviral IL-10 gene transfection can prevent the development of bronchiolitis obliterans. This is the first demonstration of a gene therapeutic strategy to treat this devastating condition which effects over 50% of lung transplant patients.
We are currently studying the effect of IL-10 transfection of the donor on ischemia reperfusion injury in order to develop a combined therapeutic approach to ischemia reperfusion injury and obliterative bronchiolitis in a lung transplant patient. We are also looking at the mechanisms of cell death related to ischemia reperfusion injury and the genes that control these processes.
James Wallace McCutcheon Chair in Surgery
Director, Toronto Lung Transplant Program
- Program Medical Director Surgical Services and Critical Care UHN
- Director, Latner Thoracic Research Laboratories
- Scientist, McEwen Centre for Regenerative Medicine
- Professor, Division of Thoracic Surgery & Institute of Biomaterials and Biomedical Engineering
University of Toronto
Additional Contact Information
Tel: 416 340 3863; Fax: 416 340 3185
190 Elizabeth St. RFE 1-408
Toronto, ON, M5G 2C4, Canada
Tel: 416 340 4010; Fax: 416 340 4556
Division of Thoracic Surgery, Toronto General Hospital
200 Elizabeth St. 9N-946
Toronto, ON, M5G 2C4, Canada
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