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August 01, 2017

New drug for an orphan bone disease

CiRA researchers use iPS cells to show rapamycin, an approved drug, may inhibit the excessive bone growth that defines the orphan disease fibrodysplasia ossificans progressiva.

With an estimated 1200 patients worldwide, fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease. In FOP patients, damage to soft tissues like muscles and ligaments are replaced with bone. The excessive bone literally causes the body to ossify to the point that patients cannot move. Because of its rarity, there is little understanding of the disease and thus little in terms of treatment. In a new study published in Journal of Clinical Investigation, Professor Junya Toguchida and Associate Professor Makoto Ikeya at the Center for iPS Cell Research and Application (CiRA) report a new drug screening system using iPS cells that reveals one drug candidate, rapamycin, could prevent the ossification seen in FOP.

The abnormal bone growth in FOP is because of a mutation in the ACVR1 gene, which causes the body to respond abnormally to trauma to soft tissue.

"The body reacts like it has a broken bone even though soft tissue is damaged. Bone grows in the soft tissue, and the patient loses mobility. Eventually the bone growth spreads so it is hard to swallow or breathe," explains Ikeya.

Toguchida and Ikeya have long worked together to study how the ACVR1 mutation causes FOP by using patient iPS cells. Although the disease is rare, Toguchida, who is also an orthopedic surgeon at Kyoto University Hospital, has had access to about half of Japan's FOP patients through patient advocacy groups, while Ikeya, a developmental biologist, has been studying the abnormal bone growth by differentiating these iPS cells into bone or soft tissue cells.

ACVR1 codes for a receptor that activates the signaling of Bone Morphogenetic Protein (BMP). BMP had been the focus of drug discovery studies until Kyosuke Hino, a visiting scientist from the Sumitomo Dainippon Pharma Corporation, showed that the ACVR1 mutation also activates the signaling of Activin-A.

"This result promotes our understanding of FOP but also at the same time provide us with candidates for therapeutic drugs. Although we know Activin-A is a trigger for bone formation in FOP, we do not know how Activin-A signal induces bone" says Toguchida.

To find drug compounds, Hino used a high-throughput drug screening (HTS) system and found rapamycin. Rapamycin is an approved drug that is commonly used to suppress immune reactions during transplants and other treatments.

"Our HTS system is unique because we can study the effect of the drug on patient cells in animal models. Usually, patient cells are tested outside a body. Plus, we searched currently marketed drugs. These drugs should accelerate clinical trials because we already know their dose levels and side effects," says Ikeya.

To validate the finding of rapamycin, the scientists tested the drug on immunodeficient mice that carried cells made from FOP patient iPS cells. These mice normally show FOP symptoms, but oral administration of rapamycin prevented the excessive bone growth. Further study showed that rapamycin did not kill the FOP patient cells but rather suppressed mTOR signaling.

"mTOR signaling regulates many systems in the body," says Toguchida. "It responds to environmental inputs like nutrients and stress. Its dysregulation causes many disorders such as cancer, diabetes and neurodegeneration. Its role in bone growth is not well studied."

Based on these findings, Toguchida has received approval from the Japanese government to start a clinical trial. This clinical trial will be the world's first for a drug that is based on results from an iPS cell-based model.

Paper Details
  • Journal: The Journal of Clinical Investigation
  • Title: Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva
  • Authors: Kyosuke Hino1,2, Kazuhiko Horigome1,2, Megumi Nishio3, Shingo Komura1,4, Sanae Nagata1, Chengzhu Zhao1, Yonghui Jin3,5, Koichi Kawakami6,7, Yasuhiro Yamada1,8, Akira Ohta1, Junya Toguchida1,3,5,9 and Makoto Ikeya1
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
    2. iPS Cell-Based Drug Discovery, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan
    3. Department of Tissue Regeneration, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
    4. Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
    5. Institute for Advancement of Clinical and Translational Science (iACT), Kyoto University Hospital, Kyoto, Japan
    6. Division of Molecular and Developmental Biology, National Institute of Genetics, Shizuoka, Japan
    7. Department of Genetics, Graduate University for Advanced Studies (SOKENDAI), Shizuoka, Japan
    8. Institute for Integrated Cell-Material Sciences (WPI-iCeMS)
    9. Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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