High-content screen identifies cyclosporin A as a novel ABCA3-specific molecular corrector

Introduction ATP-binding cassette subfamily A member 3 (ABCA3) 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 interstitial lung disease in children. Apart from lung transplantation, there is no cure available.

Methods A phenotypic cell-based assay was developed by utilizing the known ABCA3 corrector C13, the ABCA3-variant K1388N, a well-described clinically relevant trafficking mutation and machine-learning algorithms to unravel ABCA3-specific correctors by screening a library of 1,280 FDA-approved drugs.

Results To address the lack of causal therapeutic options for ABCA3 deficiency, we developed a rapid and reliable approach, which is compatible with high-content screening, by using machine-learning algorithms to autonomously identify ABCA3 wild-type-like or mutant-like cells, to investigate variant-specific molecular mechanisms and to identify pharmacological modulators for mono- or combination therapies. We identified Cyclosporin A (CsA) and validated it as a potential corrector by using previously described functional small format assays. In addition, we showed that CsA was able to correct several, but not all other mistrafficked ABCA3 variants, by enabling ABCA3 maturation to wild-type levels.

Conclusion ABCA3-deficiency is a rare clinical condition making conventional clinical studies difficult to conduct. Therefore, the screening of FDA-approved drugs and assessing their clinical value in trials may provide an intermediate step towards urgently needed treatments. Repurposing studies have the potential to bridge the time necessary for the development of new molecules, which still have a high rate of failure and take many years until patients may benefit. Hence, CsA may be a potential treatment option in ABCA3 deficiency depending on the responsiveness of the underlying mutation. This work was recently accepted in AmJRespirCellMolBiol.doi: 10.1165/rcmb.2021-0223OC.

 

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Publication History

Article published online:
21 September 2022