Shaf Keshavjee

Shaf Keshavjee, MD, MSc, FRCSC, FACS

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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 them.

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 and prolonged expression of the 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.

Currently, we are 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.

Related Links

N Engl J Med. 2016 May 12;374(19):1831-41
Cameron JI, Chu LM, Matte A, Tomlinson G, Chan L, Thomas C, Friedrich JO, Mehta S, Lamontagne F, Levasseur M, Ferguson ND, Adhikari NK, Rudkowski JC, Meggison H, Skrobik Y, Flannery J, Bayley M, Batt J, dos Santos C, Abbey SE, Tan A, Lo V, Mathur S,...
J Heart Lung Transplant. 2016 Mar 10;
Linacre V, Cypel M, Machuca T, Nakajima D, Hashimoto K, Zamel R, Chen M, Iskender I, Dos Santos P, Waddell TK, Liu M, Keshavjee S
Curr Opin Organ Transplant. 2016 Jun;21(3):329-35
Cypel M, Keshavjee S
Thorac Surg Clin. 2016 May;26(2):139-45
Cypel M, Keshavjee S
Am J Transplant. 2015 Aug;15(8):2223-30
Verleden SE, Todd JL, Sato M, Palmer SM, Martinu T, Pavlisko EN, Vos R, Neyrinck A, Van Raemdonck D, Saito T, Oishi H, Keshavjee S, Greer M, Warnecke G, Gottlieb J, Haverich A
J Heart Lung Transplant. 2016 Mar 23;
Iskender I, Sakamoto J, Nakajima D, Lin H, Chen M, Kim H, Guan Z, Del Sorbo L, Hwang D, Waddell TK, Cypel M, Keshavjee S, Liu M
Interact Cardiovasc Thorac Surg. 2016 Mar 30;
Donahoe L, Granton J, McRae K, Thenganatt J, Moric J, Keshavjee S, de Perrot M
Oncotarget. 2016 Mar 23;
Toba H, Tomankova T, Wang Y, Bai X, Cho HR, Guan Z, Adeyi OA, Tian F, Keshavjee S, Liu M
Oncotarget. 2016 Mar 25;
Sacher AG, Le LW, Lara-Guerra H, Waddell TK, Sakashita S, Chen Z, Kim L, Zhang T, Kamel-Reid S, Salvarrey A, Darling G, Yasufuku K, Keshavjee S, De Perrot M, Shepherd FA, Liu G, Tsao M, Leighl NB
Transpl Int. 2015 Jun;28(6):643-56
Van Raemdonck D, Neyrinck A, Cypel M, Keshavjee S

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Professor, Division of Thoracic Surgery & Institute of Biomaterials and Biomedical Engineering, University of Toronto