Pluripotent Stem Cell: Disease Modeling

Poster

F-3038 - PATIENT-DERIVED iPSC-BASED DRUG DISCOVERY PLATFORM HIGHLIGHTS RAPAMYCIN AS A DRUG CANDIDATE FOR FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP)

6/22/2018
19:00 - 20:00

 Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification and there is no treatment for FOP. FOP patients harbor point mutations in ACVR1 (also known as ALK2), a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render ligand-independent constitutive activity and ligand-dependent hyper activity in BMP signaling, recently, we and Hatsell et al. discovered a novel mechanism of heterotopic ossification (HO) by utilizing FOP patient-derived iPSCs (FOP-iPSCs) and FOP-ACVR1 conditional-on knock-in mice. These studies revealed that mutated FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling but not BMP signaling, and Activin-A evoked enhanced chondrogenesis of induced mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs) via BMP and TGF-β signaling.

 By utilizing FOP-iPSCs and Activin-A, we developed a robust protocol to show accelerated chondrogenesis of FOP-iMSCs in vitro and in vivo. Taking advantage of these results, here, we developed a high-throughput screening (HTS) system for FOP and identified mTOR inhibitors as drug candidates by screening a drug repositioning-focused library. Particularly, rapamycin showed potent therapeutic effect on HO in two different in vivo HO models: FOP model mice expressing FOP-ACVR1 and a FOP-iPSC-based HO model in which ectopic bones derived from FOP patient-derived cells are formed in mice. Moreover, we identified ENPP2 as a linker of FOP-ACVR1 and enhanced mTOR signaling in chondrogenesis. These results uncovered rapamycin as a promising drug candidate for FOP, and a clinical trial has been started on October 2017 in Japan.


 

Kyosuke Hino

Sumitomo Dainippon Pharma Co.,Ltd., Osaka, Japan

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    F-3038 - PATIENT-DERIVED iPSC-BASED DRUG DISCOVERY PLATFORM HIGHLIGHTS RAPAMYCIN AS A DRUG CANDIDATE FOR FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP)



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    Send Email for F-3038 - PATIENT-DERIVED iPSC-BASED DRUG DISCOVERY PLATFORM HIGHLIGHTS RAPAMYCIN AS A DRUG CANDIDATE FOR FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP)