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.
Public Health Relevance Statement: LignaMed, LLC. is developing LGM2605 as a device for use in lung transplant. In this application we propose to treat donor lungs (rather than the current clinical practice of treating the live recipient) with LGM2605, a device which blocks a cascade of damaging signals on the donor lung that predispose it to being injured after transplant. Elucidation of the mechanism by which this protection occurs is the focus of this work.
Project Terms: Adherence; Adverse effects; Affect; Anti-inflammatory; Antioxidants; Blood Vessels; Buffers; Cell Adhesion; Cell Adhesion Molecules; Cells; chemokine; chlorination; Chlorine; Clinical; clinical practice; Cryopreservation; Cysteine; cytokine; Data; Development; Devices; Donor person; Enzymes; Evaluation; Event; FDA approved; Flushing; Free Radical Scavengers; Generations; HL60; Human; Hypochlorous Acid; Immune; immunoregulation; Immunosuppression; improved; In Situ; In Vitro; in vivo; Inflammation; Inflammatory; inhibitor/antagonist; injured; Injury; Ischemia; Leadership; Lignans; Lung; Lung Inflammation; lung injury; Lung Transplantation; macrophage; Medical Device; meetings; Modeling; Monitor; monocyte; mouse model; Mus; neutrophil; Neutrophil Activation; Neutrophil Infiltration; novel; nucleobase; Operative Surgical Procedures; Organ Donor; Outcome; oxidation; oxidative damage; P-Selectin; Pathway interactions; Pennsylvania; Perfusion; Peroxidases; Phase; phase 1 study; Phenotype; Property; Protective Agents; Proteins; recruit; Regimen; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Respiratory physiology; Role; secoisolariciresinol; Signal Transduction; small molecule; Therapeutic immunosuppression; Time; Tissues; transplant model; Transplant Recipients; Transplantation; Universities; Work
