Abstract Number: PB0688
Meeting: ISTH 2021 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Rare Bleeding Disorders
Background: Replacement therapy requiring intravenous injection is the mainstay of treatment for congenital factor (F) VII deficiency. As such, there is an unmet need for new therapeutic strategies using other delivery mechanisms. Drug repurposing allows for efficient discovery and implementation of new treatments, and identification of pharmacological enhancers of FVII variant activity would be of clinical importance.
Aims: To identify clinically approved drugs that enhance the activity of the FVII variant p.Q160R.
Methods: High-throughput screening was conducted using a library of >1500 FDA-approved drugs. The primary screen was performed in conditioned medium from CHO-K1 cells transiently expressing wild-type (wt) or variant (p.Q160R) FVII. Equal amounts of FVII antigen from conditioned medium were loaded onto the assay plates. Samples were incubated with library drugs for 1.5 hours (h) at 37 °C. FVII activity was analyzed using Biophen FVII assay and absorbance measured at 405 nm for 2 h, 37 °C. Data were analyzed using KNIME software. Positive hits were verified in patient plasma.
Results: The initial velocity (V0) and absorbance (A405) at 2 h at various compound concentrations were calculated. The primary screen of conditioned media identified the orally available histone deacetylase inhibitor Abexinostat and the inhaled surfactant Tyloxapol as enhancers of the FVII variant with an EC50 of ~1 or ~3 µM, respectively. The 2 hits were verified in plasma from 7 p.Q160R variant patients. Tyloxapol showed a dose-response effect in plasma from all patients with an EC50 of ~1.5 – 2 µM. Abexinostat demonstrated a dose-response effect in 6 of 7 patients with an EC50 of ~2 µM.
Conclusions: This proof-of-concept study demonstrates that drug repurposing may be feasible for novel treatment of FVII deficiency. Clinically approved drugs can be quickly channeled for use in clinical trials or serve as templates for discovery of novel drugs for this disease.
To cite this abstract in AMA style:
Andersen E, Mowinckel MC, Stavik B, Sandset PM, Chollet ME. High-throughput Screening for Pharmacological Enhancers of Mutated Factor VII Activity [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/high-throughput-screening-for-pharmacological-enhancers-of-mutated-factor-vii-activity/. Accessed March 22, 2024.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/high-throughput-screening-for-pharmacological-enhancers-of-mutated-factor-vii-activity/