The effect of TLR4 inhibition on lung transplant ischemia-reperfusion injury

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Department of Health and Human Services
Award Year:
Phase I
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(919) 619-0388
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(919) 619-0388
Research Institute:
University Of North Carolina Chapel Hill

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Nonprofit college or university
DESCRIPTION (provided by applicant): Ischemia-reperfusion injury (IRI) occurs in organs when circulation is interrupted, causing ischemia, and then ischemic tissue is reperfused. This leads to a series of biologic consequences, resulting in edema and inflammation. IRI is a significant problem in organ transplantation, because IRI is the major cause of primary graft failure and organ dysfunction after transplant. IRI is also a major problem in many clinical scenarios, including cardiopulmonary bypass (CPB) used in cardiac surgery, myocardial infarction (MI), and stroke. There are currently no effective therapies to prevent or reduce IRI. Graft injury due to IRI at the time of implantation is now 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 LTX, 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 significant clinical impact; it could improve both short- and long-term results of conventional LTX, and it could facilitate LTX from NHBDs. In addition, reducing IRI in other organs wouldhave far-reaching implications in organ transplantation and in CPB, MI, and stroke. We have identified receptors and effector pathways of the innate immune system as important contributors to inflammation due to IRI. Among these, there is growing evidencefrom our group and others that toll-like receptor 4 (TLR4) is a critical contributor to IRI in transplant and to other IRI models. The purpose of the Phase I STTR is to determine if CRX-526, a TLR4 inhibitor that we showed prevents edema due to IRI, can ameliorate lung IRI. X-In8 is a biotechnology company whose mission is to develop strategies to temporarily turn off innate immunity to prevent IRI. Demonstrating effectiveness of CRX-526 to reduce IRI in relevant translational cell culture models of IRI andLTX models will justify Phase II studies using survival LTX models to evaluate commercial applications in the LTX market, followed by studies in other types of organ transplant and other clinical scenarios of IRI such as CPB, MI, and stroke. PUBLICHEALTH RELEVANCE: Ischemia-reperfusion injury (IRI), which occurs when blood flow stops and then starts again, causes damage to tissue or organs in heart attacks, strokes, heart bypass surgery, and organ transplantation. Toll-like receptors (TLRs) of theinnate immune system, in particular TLR4, contribute to edema and inflammation in IRI. In Phase I, we will determine the benefit of inhibiting TLR4 activation with CRX-526, an agent that we showed prevents edema due to IRI; in Phase II we plan to determineefficacy of CRX-526 in lung transplantation. This work may expand the supply of healthy lungs for transplant and could stop IRI in heart attack, stroke or heart bypass.

* information listed above is at the time of submission.

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