High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva

Disease Models & Mechanisms

Laura Tonachini¹  Renata Bocciardi¹  Serena Cappato¹  Francesca Giacopelli¹  Roberto Ravazzolo¹  Barbara Canciani²  Mario Tirone³  Luis J. V. Galietta⁴  Antonello E. Spinelli⁵  Martina Sormani⁶  Anna Giovenzana⁶  Silvia Brunelli⁶ 

[1] Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova 16132, Italy;Dipartimento di Medicina Sperimentale, Università di Genova & IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy;Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano 20132, Italy;Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy;Medical Physics Department and Centre for Experimental Imaging, San Raffaele Scientific Institute, Milano 20132, Italy;School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy;

关键词: ACVR1;    Transcriptional regulation;    BMP signaling pathway;    FOP;    Dipyridamole;    High-throughput screening;    Drug repositioning;   

DOI  :  10.1242/dmm.023929

来源: DOAJ

【 摘 要 】

The ACVR1 gene encodes a type I receptor of bone morphogenetic proteins (BMPs). Activating mutations in ACVR1 are responsible for fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by congenital toe malformation and progressive heterotopic endochondral ossification leading to severe and cumulative disability. Until now, no therapy has been available to prevent soft-tissue swelling (flare-ups) that trigger the ossification process. With the aim of finding a new therapeutic strategy for FOP, we developed a high-throughput screening (HTS) assay to identify inhibitors of ACVR1 gene expression among drugs already approved for the therapy of other diseases. The screening, based on an ACVR1 promoter assay, was followed by an in vitro and in vivo test to validate and characterize candidate molecules. Among compounds that modulate the ACVR1 promoter activity, we selected the one showing the highest inhibitory effect, dipyridamole, a drug that is currently used as a platelet anti-aggregant. The inhibitory effect was detectable on ACVR1 gene expression, on the whole Smad-dependent BMP signaling pathway, and on chondrogenic and osteogenic differentiation processes by in vitro cellular assays. Moreover, dipyridamole reduced the process of heterotopic bone formation in vivo. Our drug repositioning strategy has led to the identification of dipyridamole as a possible therapeutic tool for the treatment of FOP. Furthermore, our study has also defined a pipeline of assays that will be useful for the evaluation of other pharmacological inhibitors of heterotopic ossification.

【 授权许可】

Unknown