Research Project
7750074
DESCRIPTION (provided by applicant): Ischemia-reperfusion injury (IRI) is a major problem in many clinical scenarios, including myocardial infarction and stroke. IRI is also a major problem in organ transplantation, because IRI is the major cause of primary graft failure and organ dysfunction after transplant. Increasingly, graft injury due to IRI at the time of implantation is recognized as a major contributor to delayed graft dysfunction, also known as chronic rejection. Lung transplantation (LTX) has extended and improved the lives of thousands of patients with end-stage lung disease, but is severely constrained by an inadequate supply of suitable donors from conventional organ donors (brain-dead, ventilated patients whose organs are retrieved after controlled cardiac arrest). Among solid organs transplanted, lungs have one of the highest rates of acute graft failure, and the highest incidence of late graft failure. Hundreds of transplant candidates die every year before receiving transplants, and thousands of others are not even considered candidates because of the lung donor shortage. If lungs could be retrieved from non-heart-beating donors (NHBDs) - victims of sudden death - at intervals after circulatory arrest and transplanted safely, the shortage of lungs for transplant could be eliminated, and the lives of thousands more patients with end-stage lung disease could be extended or enhanced by LTX. Transplant using lungs retrieved from NHBDs is also associated with IRI. Any therapy to reduce lung IRI would have considerable clinical importance;it could improve both short- and long-term results of conventional LTX, and it could facilitate LTX from NHBDs. In addition, if this therapy could reduce IRI in other organs, it would have far-reaching implications in the field of organ transplantation and other areas of clinical medicine. Because of our interest in transplanting lungs retrieved from NHBDs, we have studied lung IRI extensively, and have implicated effector pathways of the innate immune system as important contributors to inflammation due to IRI. Among these, there is growing evidence from our group and others that activation of the ubiquitous transcription factor nuclear factor kappa-B (NF-(B) is a critical contributor to IRI in transplantation and other IRI models. The purpose of the Phase I STTR is to determine if inhibition of NF-(B can ameliorate lung IRI. We have initiated a collaboration with TheraLogics, a biotechnology company, to evaluate the effectiveness of two agents to inhibit activation of NF-(B: NEMO binding peptides that block NF-(B activation by interfering with the interaction of IKK( with IKK( and IKK(;and Compound A, a low molecular weight inhibitor of IKK(. TheraLogics has exclusive licenses for both of these potent inhibitors of NF-(B. We will use both inhibitors in Phase I studies. We will select the most efficacious inhibitor for Phase II studies. If these Phase I studies are successful, Phase II studies in translational lung transplant models will pave the way for clinical trials in lung transplantation, lung transplantation from NHBDs, and studies in other types of organ transplant and other clinical scenarios of IRI. PUBLIC HEALTH RELEVANCE: Ischemia-reperfusion injury (IRI) is a major problem in many clinical scenarios, including myocardial infarction, stroke, and organ transplantation, where IRI is the major cause of primary graft failure;it is also a major contributor to delayed graft dysfunction, also known as chronic rejection. Because activation of the ubiquitous transcription factor nuclear factor kappa-B (NF-(B) is implicated in IRI and organ transplantation, this proposal outlines experiments to determine the impact of inhibiting NF-(B activation, through collaboration of a university-based expert in lung IRI and transplantation, and TheraLogics, a biotechnology company with exclusive licenses for two potent inhibitors of NF-(B: a NEMO binding peptide and a low molecular weight inhibitor of IKK( (license for this compound is being renewed). In Phase I, we propose to evaluate both agents in established in vitro and in vivo models of lung IRI due to transplant, and if we determine a benefit of NF-(B inhibition, in Phase II we propose to determine efficacy of the most effective agent in clinically relevant survival lung transplant models.
