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Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation.
J Bone Miner Res. 2016 09; 31(9):1666-75.JB

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. © 2016 American Society for Bone and Mineral Research.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

26896819

Citation

Chakkalakal, Salin A., et al. "Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 31, no. 9, 2016, pp. 1666-75.
Chakkalakal SA, Uchibe K, Convente MR, et al. Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation. J Bone Miner Res. 2016;31(9):1666-75.
Chakkalakal, S. A., Uchibe, K., Convente, M. R., Zhang, D., Economides, A. N., Kaplan, F. S., Pacifici, M., Iwamoto, M., & Shore, E. M. (2016). Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 31(9), 1666-75. https://doi.org/10.1002/jbmr.2820
Chakkalakal SA, et al. Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation. J Bone Miner Res. 2016;31(9):1666-75. PubMed PMID: 26896819.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation. AU - Chakkalakal,Salin A, AU - Uchibe,Kenta, AU - Convente,Michael R, AU - Zhang,Deyu, AU - Economides,Aris N, AU - Kaplan,Frederick S, AU - Pacifici,Maurizio, AU - Iwamoto,Masahiro, AU - Shore,Eileen M, Y1 - 2016/03/12/ PY - 2015/11/02/received PY - 2016/02/12/revised PY - 2016/02/18/accepted PY - 2016/2/21/entrez PY - 2016/2/21/pubmed PY - 2017/12/19/medline KW - ACVR1 KW - FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP) KW - HETEROTOPIC OSSIFICATION KW - PALOVAROTENE KW - RETINOIC ACID RECEPTOR (RAR) SP - 1666 EP - 75 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 31 IS - 9 N2 - 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. © 2016 American Society for Bone and Mineral Research. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/26896819/Palovarotene_Inhibits_Heterotopic_Ossification_and_Maintains_Limb_Mobility_and_Growth_in_Mice_With_the_Human_ACVR1_R206H__Fibrodysplasia_Ossificans_Progressiva__FOP__Mutation_ L2 - https://doi.org/10.1002/jbmr.2820 DB - PRIME DP - Unbound Medicine ER -