Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva
Eleanor Williams, Jana Bagarova, Georgina Kerr, Dong-Dong Xia, Elsie S. Place, Devaveena Dey, Yue Shen, Geoffrey A. Bocobo, Agustin H. Mohedas, Xiuli Huang, Philip E. Sanderson, Arthur Lee, Wei Zheng, Aris N. Economides, James C. Smith, Paul B. Yu, Alex N. Bullock
Eleanor Williams, Jana Bagarova, Georgina Kerr, Dong-Dong Xia, Elsie S. Place, Devaveena Dey, Yue Shen, Geoffrey A. Bocobo, Agustin H. Mohedas, Xiuli Huang, Philip E. Sanderson, Arthur Lee, Wei Zheng, Aris N. Economides, James C. Smith, Paul B. Yu, Alex N. Bullock
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Research Article Bone biology Therapeutics

Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva

Abstract

Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues owing to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2 (also known as ACVR1). From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2, compared with other receptors of the BMP/TGF-β signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1Q207D-transgenic mouse line, which provides a model of heterotopic ossification (HO), as well as an inducible ACVR1R206H-knockin mouse, which serves as a genetically and physiologically faithful FOP model. In both models, saracatinib was well tolerated and potently inhibited the development of HO, even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in FOP treatment, offering an accelerated path to clinical proof-of-efficacy studies and potentially significant benefits to individuals with this devastating condition.

Authors

Eleanor Williams, Jana Bagarova, Georgina Kerr, Dong-Dong Xia, Elsie S. Place, Devaveena Dey, Yue Shen, Geoffrey A. Bocobo, Agustin H. Mohedas, Xiuli Huang, Philip E. Sanderson, Arthur Lee, Wei Zheng, Aris N. Economides, James C. Smith, Paul B. Yu, Alex N. Bullock

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Figure 5

Dose-dependent in vivo efficacy of saracatinib in the FOP-knockin mouse model.

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Dose-dependent in vivo efficacy of saracatinib in the FOP-knockin mouse ...
Neonatal Acvr1[R206H]FlEx/+] mice were injected with a low dose of Ad.Cre (1 × 108 PFU i.m. P7) and treated with 25 mg/kg/d saracatinib or vehicle orally for 28 days (grey shaded region) and observed for a total of 90 days. Representative mice are shown with x-ray radiography, Micro-CT, and Alizarin red hindlimb prep. (A) Sixty percent of vehicle-treated mice (3/5) developed HO and severe loss of passive range of motion at 90 days (original magnification, ×0.7). Treatment with saracatinib prevented radiographic HO in 5/5 treated mice, and (B) preserved range of motion in 4/5 mice at 90 days (2-way ANOVA with Sidak’s test for multiple comparisons, **P < 0.01, day 61; ****P < 0.0001, day 90 vs. control), data depicted as median ± IQR, n as indicated. ACVR1[R206H]FlEx/+-knockin mice were injected with a high dose of Ad.Cre (5 × 109 PFU i.m. P7) and treated with varying doses of saracatinib or vehicle orally for 40 days. Radiographic HO and associated impaired range of motion were observed to progress over 40 days of treatment. Treatment with saracatinib at 2.5, 5, and 10 mg/kg/d protected mice from radiographic HO, and preserved passive range of motion (C–E). Two-way with Dunnett’s test for multiple comparisons. (C) *P < 0.05, days 14–15, 24–25, and 27–28; ***P < 0.001, days 19–23; ****P < 0.0001, days 29–39 vs. vehicle treatment. (D) ***P < 0.001, days 19–24; **P < 0.01, days 29–34; ****P < 0.0001, days 35–39 vs. vehicle treatment. (E) *P < 0.05, days 19–24; **P < 0.01, days 29–33; ****P < 0.0001, days 34–39 vs. vehicle treatment. Data depicted as median ± IQR, n as indicated.