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J Bone Miner Res. 2016 Sep;31(9):1666-75. doi: 10.1002/jbmr.2820. Epub 2016 Mar 12.

Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation.

Author information

1
Department of Orthopedic Surgery, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.
2
The Center for Research in FOP and Related Disorders, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.
3
The Children's Hospital of Philadelphia, Division of Orthopedic Surgery, Philadelphia, PA, USA.
4
Regeneron Pharmaceuticals, Tarrytown, NY, USA.
5
Department of Medicine, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.
6
Department of Genetics, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.

Abstract

Fibrodysplasia ossificans progressiva (FOP), a rare and as yet untreatable genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification (HO) in humans and causes skeletal deformities, movement impairment, and premature death. Most FOP patients carry an activating mutation in a bone morphogenetic protein (BMP) type I receptor gene, ACVR1(R206H) , that promotes ectopic chondrogenesis and osteogenesis and, in turn, HO. We showed previously that the retinoic acid receptor γ (RARγ) agonist palovarotene effectively inhibited HO in injury-induced and genetic mouse models of the disease. Here we report that the drug additionally prevents spontaneous HO, using a novel conditional-on knock-in mouse line carrying the human ACVR1(R206H) mutation for classic FOP. In addition, palovarotene restored long bone growth, maintained growth plate function, and protected growing mutant neonates when given to lactating mothers. Importantly, palovarotene maintained joint, limb, and body motion, providing clear evidence for its encompassing therapeutic potential as a treatment for FOP.

KEYWORDS:

ACVR1; FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP); HETEROTOPIC OSSIFICATION; PALOVAROTENE; RETINOIC ACID RECEPTOR (RAR)

PMID:
26896819
PMCID:
PMC4992469
DOI:
10.1002/jbmr.2820
[Indexed for MEDLINE]
Free PMC Article

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