Graft-protective properties of LGM2605 in Lung Transplantation

Lignamed, Llc, Philadelphia PA

Investigators

Abstract

LignaMed, LLC is developing LGM2605; a novel medical device that will be administered via an FDA approved ex vivo lung perfusion device (EVLP) to improve lung function parameters of ex vivo donor lungs in advance of transplant surgery. Per FDA device regulations LGM2605 will be fully flushed and cleared from the donor lung prior to transplant. The major challenge with lung transplantation is the oxidative damage that occurs during lung storage. This reduces the availability of lungs for transplant and ?primes? the donor lung to recruit polymorphonuclear neutrophils (PMN) from the transplant recipient. Recruited PMN adhere to the vessel wall of the newly transplanted lung (graft), transmigrate and release myeloperoxidase (MPO), an enzyme stored in neutrophils and macrophages responsible for hypochlorous acid generation causing injury to the graft. Recognizing the role of PMN in injury and eventual poor transplant outcome, the clinical strategy at present is to block PMN activation by a non-specific immunosuppression regimen administered to the transplant recipient. However, immunosuppression therapy has severe side effects. LignaMed proposes the use of LGM2605, a synthetic small molecule agent to a) dampen inflammatory pathways in the donor lung and b) inhibit MPO activation in recruited PMN. Preliminary data show that LGM2605 protects human donor lungs but the mechanism of protection has not been elucidated. In the proposed Phase I study we will determine the immunomodulatory properties of LGM2605 to modulate the pro-inflammatory phenotype of stored human and mouse donor lungs (cold storage) (Aim 1) and reduce PMN adherence and activation during warm reperfusion by monitoring (exogenous) PMN adherence, MPO inhibition and subsequent lung injury (Aim 2). If data obtained from the proposed human and mouse donor lungs show a significant reduction in PMN recruitment, adherence and subsequent tissue injury, we will be enabled to proceed to Phase II with a full clinical and analytical evaluation of this agent for an eventual FDA approval. Our focus on ?pre-treatment? of a donor organ (prior to transplant) with LGM2605 constitutes a paradigm shift from the current transplant related therapies.