Palovarotene (Sohonos), a synthetic retinoid for reducing new heterotopic ossification in fibrodysplasia ossificans progressiva: history, present, and future.

Autor:	Hsiao EC; Division of Endocrinology and Metabolism, Department of Medicine; the Program in Craniofacial Biology; The Institute for Human Genetics; and The Ely and Edythe Broad Institute for Regeneration Medicine, University of California-San Francisco, San Francisco, CA 94143, United States., Pacifici M; Translational Research Program in Pediatric Orthopedics, Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States.
Jazyk:	angličtina
Zdroj:	JBMR plus [JBMR Plus] 2024 Nov 19; Vol. 9 (1), pp. ziae147. Date of Electronic Publication: 2024 Nov 19 (Print Publication: 2025).
DOI:	10.1093/jbmrpl/ziae147
Abstrakt:	Retinoids are metabolic derivatives of vitamin A and play crucial roles in the regulation of various tissues and organs during prenatal and postnatal development. Active retinoids, like all-trans-retinoic acid, are synthesized in the cytoplasm and subsequently interact with nuclear retinoic acid receptors (RARα, RARβ, and RARγ) to enhance transcription of specific genes. In the absence of retinoids, RARs can still bind to response elements of target genes but repress their transcription. Chondrogenic cell differentiation and cartilage maturation in the growth plate require the absence of retinoid signaling and transcriptional repression by unliganded RARs. This led to the hypothesis that synthetic retinoid agonists may be pharmacological agents to inhibit those cellular processes and counter the excessive formation of cartilage and bone in conditions like heterotopic ossification (HO). HO can be instigated by diverse culprits including trauma, invasive surgeries, inflammatory disorders, or genetic conditions. One such genetic disease is fibrodysplasia ossificans progressiva (FOP), a rare disorder driven by activating mutations in the ACVR1 gene. Patients with FOP have severe and progressive HO formation in soft tissues, leading to extensive permanent loss of mobility and increased mortality. Synthetic retinoid agonists selective for RARα or RARγ showed efficacy against injury-induced and genetic HO in mouse models. The RARγ agonists showed the highest effectiveness, with palovarotene being selected for clinical trials in patients with FOP. Post hoc analyses of phase II and phase III clinical trials showed that palovarotene has significant disease-modifying effects for FOP, but with significant risks such as premature growth plate closure in some younger subjects. This review provides an overview of retinoid and RAR roles in skeletal development and discusses the identification of palovarotene as a potential FOP therapy, the clinical data supporting its regulatory approval in some countries, and the potential applications of this drug for other relevant disorders besides FOP. Competing Interests: E.C.H. serves in an unpaid capacity on the Medical Registry Advisory Board of the International Fibrodysplasia Ossificans Progressiva Association; the Fibrous Dysplasia Foundation Medical Advisory Board; and the International Clinical Council on FOP. E.C.H. receives clinical trials support through his institution from Clementia Pharmaceuticals, an Ipsen Company; Ipsen Pharmaceuticals; Ascendis Bio, and āshibio. Ipsen Pharmaceuticals is the manufacturer of palovarotene. M.P. has nothing to disclose. (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)
Databáze:	MEDLINE
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