Repurposing existing Sphingosine-1-phosphate receptor modulators to reduce risk of primary graft dysfunction (PGD) after lung transplantation

Context: Lung transplantation remains the only realistic option for selected patients with end-stage respiratory disease. However, despite substantial demand, more than 80% of lungs from brain dead donors (DBD) offered are turned down as unsuitable. This is largely because the lungs are highly susceptible to injury, which impairs function and negatively affects transplant outcomes. The pulmonary endothelium plays a critical role in ischaemia reperfusion injury (IRI) after lung transplantation which is characterised by development of pulmonary oedema leading to primary graft dysfunction (PGD). Severe PGD is associated with a significant increased risk of early mortality and directly reduces late survival. Furthermore, transplant patients with PGD will experience protracted mechanical ventilation and inpatient hospital care, as well as increased risk of multi-organ failure. There is both a scarcity of suitable lungs for transplantation and a need to prolong their functionality after transplantation. There are currently no condition-specific therapeutics available to prevent or treat the condition. Recent advances: Normothermic ex-vivo lung perfusion (EVLP) provides an ideal platform for administration of therapies to donor lungs prior to transplantation to improve their function and increase utilisation of donor organs (PMID:28551353). We have established a programme of experimental human EVLP with a novel paired single-lung perfusion model that allows, interventions to be assessed with each donor acting as their own control (PMID:37143202). Endothelial dysfunction represents a significant problem during pulmonary IRI. Sphingosine-1-phosphate receptor-1 (S1PR1) expressed on endothelial cells plays a fundamental role in maintaining barrier integrity. Our group has in vitro and in vivo data showing that agonism of S1PR1 can augment endothelial barrier function (PMID: 37446370). We have further evaluated S1PR1 agonism in a human split EVLP model where it showed that S1PR1 agonist (CYM5442) protects vascular endothelial barrier integrity and limits pulmonary oedema formation. Inflammatory cytokine release was also significantly reduced by the end of perfusion. This study is the first to confirm the therapeutic potential of targeting S1PR1 during human EVLP. Although our proof-of-concept data is promising, CYM5442 also demonstrated functional antagonism at higher doses in vitro. We need to identify a more-long acting S1PR1 agonist with a wider therapeutic dose range, that will cause reduced receptor desensitization. We will therefore screen a range of potential candidates, including some recently clinically approved S1PR1 agonists and those in trials. Challenge the project addresses: We aim to develop a therapeutic intervention that can be administered to the human donor lungs during EVLP prior to transplantation. This could help to protect lungs from PGD following implantation and therefore, increase the quality and number of donor lungs accepted for transplant and reduce waiting list mortality. Aims and objectives: Evaluation of the S1PR1 agonists including recently approved drugs for G-protein activation and reduced desensitisation in vitro. Use an in vitro model of IRI to optimise parameters for targeting S1P pathways to reduce deleterious consequences of IRI. Using novel human split lung EVLP model. Assess the impact of the lead compound identified above on function, pulmonary oedema and inflammation in human lungs. Dissect the inflammatory pathways involved. Potential applications and benefits: The development of new therapeutics that can improve the integrity of the vascular endothelium in donor lungs would address a major unmet need in lung transplantation by reducing the chance of PGD and early post-transplant mortality and protect long-term function of the lungs.