LU2025-192
INVENTORS
Youyang Zhao
Colin Evans
SHORT DESCRIPTION
This invention identifies endothelial ALOX15 and its lipid product, 1-Palmitoyl-2-Oleoyl-3-Arachidonoyl-rac-glycerol (POLAR), as key targets for treating sepsis and acute respiratory distress syndrome (ARDS).
BACKGROUND
Sepsis-induced acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), including severe forms like COVID-19-associated ARDS, are medical emergencies characterized by severe inflammatory lung injury and high mortality rates. A common and detrimental feature in these patients is widespread pulmonary thrombosis and associated thrombocytopenia, which paradoxically correlate with worse outcomes. Despite the significant unmet medical need, existing therapeutic approaches have largely failed to improve patient survival. Current treatments are primarily supportive, and anti-inflammatory strategies have shown limited efficacy. Furthermore, broad-spectrum anticoagulant therapies, which might seem intuitive given the prevalence of thrombosis, have repeatedly failed in clinical trials, highlighting a fundamental challenge in understanding and effectively managing the complex interplay of inflammation and coagulation in these devastating conditions.
ABSTRACT
A central discovery of this invention is that mild-to-moderate pulmonary thrombosis paradoxically protects against inflammatory lung injury by sustaining ALOX15 gene expression in endothelial cells, thereby reducing endothelial apoptosis. The inventors identified POLAR and POLAR analogs as the key downstream effectors of the protective ALOX15 pathway. Therapeutic administration of POLAR preserved vascular endothelial barrier function and inhibited lung injury in preclinical models of sepsis. Thus, treatment with POLAR or its analogs aim to inhibit thrombosis-augmented inflammatory lung injury and preserve vascular endothelial barrier function, addressing the severe lung damage seen in these conditions.
APPLICATIONS
Therapeutics for severe inflammatory lung diseases, such as sepsis, ARDS, and severe pneumonia
Therapeutics for vascular diseases beyond the lung, aimed at preserving vascular endothelial barrier function and modulating thrombosis
ADVANTAGES
Targeted endothelial protection to preserve vascular integrity and reduce lung injury
Novel therapeutic mechanism offers a new pathway to target inflammation and tailor therapy based on patient-specific responses
Reduced dependence on mechanical ventilation, which can exacerbate lung injury
Mitigates thrombocytopenia challenges that may complicate treatment
IP STATUS
A provisional patent has been filed.