New preclinical research provides support to a drug that has been repurposed to possibly treat a rare and extremely disabling genetic bone disease, particularly in children. In that disease, fibrodysplasia ossificans progressiva (FOP), a mutation triggers bone growth in muscles, alters skeletal bone formation, and limits motion, breathing, and swallowing, among a host of progressive symptoms. The research appeared online in the Journal of Bone and Mineral Research (JBMR) ahead of the print issue.

“This is the first study to show in a mouse model with the same mutation that causes FOP in people that the drug palovarotene inhibits and abates extra-skeletal bone formation, yet is protective for normal skeletal bone growth,” said senior coauthor Eileen M. Shore, PhD, the Cali/Weldon Professor of Orthopaedics and Genetics at the Center for Research in FOP and Related Disorders in the Perelman School of Medicine at the University of Pennsylvania. Another coauthor from Penn Medicine, Frederick S. Kaplan, MD, the Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine and Chief of the Division of Molecular Orthopaedic Medicine, is a world expert in heterotopic ossification (HO), the abnormal buildup of bone that occurs in FOP.

 “This work represents a big step toward therapy,” said senior coauthor, Maurizio Pacifici, PhD, a developmental biologist and Director of Orthopedic Research in the Division of Orthopedic Surgery at The Children’s Hospital of Philadelphia (CHOP). “The mice used in this study were engineered to carry the human mutation that causes FOP, and the drug showed powerful benefits. If these results translate to humans, we may be able to treat children with FOP early in life, before the disease progresses.” Masahiro Iwamoto, DDS, PhD, from CHOP, is also a senior coauthor on the study.

The team tested the effects of palovarotene, a drug previously tested in adults with emphysema. Although the drug was not developed beyond phase 2 trials for that indication, it showed few side effects. Palovarotene is a retinoic acid receptor (RAR) agonist, a molecule that binds a nuclear receptor to trigger molecular events that regulate cell function.

Palovarotene is a class of drug that selectively targets a pathway involved in cartilage formation. RAR molecules are abundant in the nucleus of cartilage cells, hence the targeted response of the drug. Pacifici and Iwamoto showed in 2011 that palovarotene inhibited extra bone growth in mice genetically engineered to model HO. The extra bone that appears in FOP flare-ups progresses through a cartilage stage before replacement with mature bone cells, following a sequence of bone formation seen during normal skeletal development.

Click here to view the full release.