Identification and evaluation of Pharmacological enhancers of the factor VII p.Q160R variant

Congenital factor (F) VII deficiency is caused by mutations in the F7 gene. The p.Q160R variant manifests with bleeding episodes due to reduced FVII activity and antigen in patient plasma, most likely caused by protein misfolding and intracellular retention. As current replacement therapy is expensive and requires frequent intravenous injections, there is an unmet need for new and less invasive therapeutic strategies. Drug repurposing allows for rapid, more cost-effective discovery and implementation of new treatments, and identification of pharmacological enhancers of FVII variant activity would be of clinical importance. High-throughput screening of > 1800 FDA-approved drugs identified the orally available histone deacetylase inhibitor abexinostat and the inhaled surfactant tyloxapol as enhancers of FVII p.Q160R variant activity. The positive hits were verified in an in vitro cell model transiently expressing wild type or variant FVII and ex vivo in patients' plasma. Both drugs showed a dose-response effect on FVII antigen and activity levels in conditioned cell medium and on FVII activity in patients' plasma. In conclusion, the efficacy of the FDA-approved drugs abexinostat and tyloxapol in enhancing FVII variant activity constitute a proof of principle for high-throughput identification of drugs that may be feasible for novel treatment of FVII deficiency.