Project 170846

Lung transplantation (LTx) has become life saving therapy for patients suffering from many types of end-stage lung diseases (e.g. emphysema, pulmonary fibrosis, pulmonary hypertension and cystic fibrosis). Most patients that are fortunate enough to receive new lungs are alive 5 years after transplantation with a much improved quality of life. Unfortunately, the number of patients requiring LTx largely exceeds the number of lung donors available. As a result, the death rate on the waiting list is 20%-30% in most lung transplant centers. Clearly, the best alternative will be to expand the number of donors. Indeed, on average we currently are able to transplant only 15% - 25% of the lungs that are offered to us from brain dead donors; 75 - 85% of donor lungs cannot be used because they are damaged (e.g. inflammation, pneumonia, etc.). Attempts to use these lungs for transplantation carry a risk of increased complications. Hence, strategies to repair injured donor lungs would significantly increase the number and safety of LTx performed every year. Our project aims to develop a new strategy of donor lung treatment and repair using ex vivo (outside the body) gene therapy (a beneficial gene is inserted into the lungs cells which in turn produce a new protein in order to heal the surrounding cells). Damaged pig and human lungs will be placed in a special pump perfusion system (that simulates physiologic conditions) and treated with IL-10 (a potent anti-inflammatory molecule) gene therapy. We will be able to evaluate the lung function in this system to document improved lung function and then confirm improved function after transplantation. We will also find new markers of donor lung injury and repair, so that in the future only truly repairable donor lungs will be used. The consequent improvement in the quality of donor lungs with ex vivo assessment and gene therapy will have a significant impact in improving outcomes of lung transplantation

ex vivo gene therapy system for donor lung repair using pump perfusion and IL-10 gene therapy