Thursday, January 2, 2025
1/2/2025
Project Summary Lung transplantation is the only treatment option for patients with end-stage lung disease. However, transplant outcomes are significantly limited by the development of primary graft dysfunction (PGD), chronic lung allograft dysfunction (CLAD), and complete organ rejection. With increasing lung transplant activity around the world, new advancements are urgently needed to improve patient survival and quality of life. At University Health Network (UHN), our team pioneered the Toronto Ex Vivo Lung Perfusion (EVLP) System—a breakthrough technology whereby donor lungs are preserved in a functional physiological state at 37°C and provided oxygen, nutrients, and other critical resources prior to transplantation. This enables donor lungs to “breathe” outside of the body for up to 12 hours. Using EVLP, transplant teams can more objectively assess marginal donor lungs and apply novel repair therapies. To this end, our project will leverage EVLP to develop novel somatic cell gene editing (SCGE) therapeutic strategies that can be applied to further enhance donor lungs. In preliminary research, we have shown that: 1) upregulation of an anti-inflammatory cytokine called interleukin (IL)-10 improves lung quality and post- transplant outcomes; and 2) recipient regulatory T cells (Tregs) that are resistant to tacrolimus (Tac) improve the regulatory microenvironment in the transplanted organ. Our hypothesis is that applying SCGE techniques during EVLP will enhance IL-10 gene and Treg cell therapies, which will immunomodulate the donor organ and lessen the risk of transplant rejection. In Aim 1, we will engineer new CRISPR editing technologies for use during EVLP and assess the feasibility and therapeutic potential of this approach using pre-clinical in vivo models. In Aim 2, we will confer Tac resistance in Treg cells using base editing and assess Treg efficacy in vivo using a human skin xenograft model. In Aim 3, we will conduct proof-of-concept translational studies and assess the efficacy of our combined therapies using clinically declined human lungs on EVLP, representing the closest approximation prior to clinical application. In our continued leadership of the field, we will enhance our strategic collaboration with Massachusetts General Hospital to explore this multidisciplinary approach to long-term transplant tolerance. Our project goal to combine SCGE and EVLP strategies will enable a grander pursuit of our long-term ambition: to ‘design’ better lungs that will last a lifetime in the transplant recipient. Achievement of our proposed objectives will result in novel clinical applications and a paradigm shift in how we treat lung transplant recipients—away from a life of immunosuppressive medications and towards self-sustaining and long-term graft tolerance.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).