High-Content Screening Identifies Cyclosporin A as a Novel ABCA3-Specific Molecular Corrector

ABCA3 (ATP-binding cassette subfamily A member 3) is a lipid transporter expressed in alveolar type II cells and localized in the limiting membrane of lamellar bodies. It is crucial for pulmonary surfactant storage and homeostasis. Mutations in the ABCA3 gene are the most common genetic cause of respiratory distress syndrome in mature newborns and of interstitial lung disease in children. To address the lack of causal therapeutic options for ABCA3 deficiency, a rapid and reliable approach is needed to investigate variant-specific molecular mechanisms and identify pharmacologic modulators for monotherapies or combination therapies. To this end, the study aimed to develop a phenotypic cell-based assay to identify ABCA3 wild autonomously–type–or mutant-like cells by using machine learning algorithms to identify morphologic differences in wild-type and mutant cells. Cyclosporin A was identified as a potent corrector, specific for some but not all ABCA3 variants. Results were validated by using previously established functional small-format assays. Hence, cyclosporin A may be selected for orphan drug evaluation in controlled repurposing trials in patients.