| Reference | [1]. Curr Opin Investig Drugs. 2009 Nov;10(11):1243-50.<br />
Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema.<br />
Hind M(1), Stinchcombe S.<br />
Author information: (1)Royal Brompton Hospital, Biomedical Research Unit, Department of Respiratory Medicine, and National Heart and Lung Institute, Imperial College, Fulham Road, London, SW3 6NP, UK. [email protected]<br />
Emphysema is characterized by the destruction of alveoli and alveolar ducts within the lungs. Retinoid signaling is believed to play a role in alveologenesis, with the retinoic acid receptor gamma thought to be required for alveolar formation. Based on this hypothesis, Roche Holding AG is developing palovarotene (R-667, RO-3300074), a selective retinoic acid receptor gamma agonist for the treatment of emphysema. In small animal studies, palovarotene was claimed to reverse the structural, functional and inflammatory features of cigarette smoke-induced emphysema. Phase I clinical trials of palovarotene in patients with emphysema demonstrated that the drug is well tolerated, with improvements observed in markers of emphysema progression. Unlike all-trans retinoic acid, the pharmacokinetic profile of palovarotene appears to be dose-proportional. At the time of publication, a phase II, placebo-controlled trial was ongoing, and was expected to report prospective measurements of exercise, gas transfer and lung densitometry endpoints. The development of a selective retinoic acid receptor gamma agonist for the treatment of emphysema represents the first of a new class of small-molecule regenerative therapies that may prove useful for the treatment of destructive or age-related lung disease.<br />
PMID: 19876792<br />
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[2]. J Orthop Res. 2018 Apr;36(4):1135-1144. doi: 10.1002/jor.23747. Epub 2017 Nov 16.<br />
Palovarotene inhibits connective tissue progenitor cell proliferation in a rat model of combat-related heterotopic ossification.<br />
Wheatley BM(1)(2), Cilwa KE(1), Dey D(1), Qureshi AT(1), Seavey JG(1)(2), Tomasino AM(1), Sanders EM(1), Bova W(3), Boehm CA(3), Iwamoto M(4), Potter BK(2), Forsberg JA(1)(2), Muschler GF(3)(5), Davis TA(1)(2).<br />
Author information: (1)Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland. (2)Orthopaedics, Uniformed Services University-Walter Reed Department of Surgery, Bethesda, Maryland. (3)Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio. (4)Department of Orthopaedics, University of Maryland, Baltimore, Maryland. (5)Department of Orthopaedic Surgery, Cleveland Clinic, Cleveland, Ohio.<br />
Heterotopic ossification (HO) develops in the extremities of wounded service members and is common in the setting of high-energy penetrating injuries and blast-related amputations. No safe and effective prophylaxis modality has been identified for this patient population. Palovarotene has been shown to reduce bone formation in traumatic and genetic models of HO. The purpose of this study was to determine the effects of Palovarotene on inflammation, progenitor cell proliferation, and gene expression following a blast-related amputation in a rodent model (n = 72 animals), as well as the ability of Raman spectroscopy to detect early HO before radiographic changes are present. Treatment with Palovarotene was found to dampen the systemic inflammatory response including the cytokines IL-6 (p = 0.01), TNF-α (p = 0.001), and IFN-γ (p = 0.03) as well as the local inflammatory response via a 76% reduction in the cellular infiltration at post-operative day (POD)-7 (p = 0.03). Palovarotene decreased osteogenic connective tissue progenitor (CTP-O) colonies by as much as 98% both in vitro (p = 0.04) and in vivo (p = 0.01). Palovarotene treated animals exhibited significantly decreased expression of osteo- and chondrogenic genes by POD-7, including BMP4 (p = 0.02). Finally, Raman spectroscopy was able to detect differences between the two groups by POD-1 (p < 0.001). These results indicate that Palovarotene inhibits traumatic HO formation through multiple inter-related mechanisms including anti-inflammatory, anti-proliferative, and gene expression modulation. Further, that Raman spectroscopy is able to detect markers of early HO formation before it becomes radiographically evident, which could facilitate earlier diagnosis and treatment. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1135-1144, 2018.<br />
DOI: 10.1002/jor.23747 PMID: 28960501<br />
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[3]. Elife. 2018 Sep 18;7:e40814. doi: 10.7554/eLife.40814.<br />
Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity.<br />
Lees-Shepard JB(1), Nicholas SE(1), Stoessel SJ(1), Devarakonda PM(1), Schneider MJ(1), Yamamoto M(1), Goldhamer DJ(1).<br />
Author information: (1)Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, United States.<br />
Comment in Elife. 2019 Jan 30;8: Elife. 2019 Jan 30;8:null.<br />
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by debilitating heterotopic ossification (HO). The retinoic acid receptor gamma agonist, palovarotene, and antibody-mediated activin A blockade have entered human clinical trials, but how these therapeutic modalities affect the behavior of pathogenic fibro/adipogenic progenitors (FAPs) is unclear. Using live-animal luminescence imaging, we show that transplanted pathogenic FAPs undergo rapid initial expansion, with peak number strongly correlating with HO severity. Palovarotene significantly reduced expansion of pathogenic FAPs, but was less effective than activin A inhibition, which restored wild-type population growth dynamics to FAPs. Palovarotene pretreatment did not reduce FAPs' skeletogenic potential, indicating that efficacy requires chronic administration. Although palovarotene inhibited chondrogenic differentiation in vitro and reduced HO in juvenile FOP mice, daily dosing resulted in aggressive synovial joint overgrowth and long bone growth plate ablation. These results highlight the challenge of inhibiting pathological bone formation prior to skeletal maturation.<br />
DOI: 10.7554/eLife.40814 PMCID: PMC6143342 PMID: 30226468<br />
Conflict of interest statement: JL, SN, SS, PD, MS, MY No competing interests declared, DG The work was funded, in part, by a sponsored research agreement with Clementia Pharmaceuticals.<br />
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[4]. Elife. 2019 Jan 30;8:e43928. doi: 10.7554/eLife.43928.<br />
Response to comment on 'Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity'.<br />
Goldhamer DJ(1), Lees-Shepard JB(1).<br />
Author information: (1)Department of Molecular and Cell Biology, University of Connecticut, Storrs, United States.<br />
Comment on Elife. 2018 Sep 18;7: Elife. 2019 Jan 30;8:<br />
We respond to concerns expressed by Pacifici and Shore (2019) about a recent paper (Lees-Shepard and Goldhamer, 2018a) in which we reported that the drug palovarotene can have severe side effects in a mouse model of fibrodysplasia ossificans progressiva.<br />
DOI: 10.7554/eLife.43928 PMCID: PMC6353591 PMID: 30698142<br />
Conflict of interest statement: DG No competing interests declared, JL is currently a scientist at Regeneron Pharmaceuticals, who are currently conducting trials for a drug treatment for FOP. The work reported in Lees-Shepard et al. (2018a), as well as the preliminary data noted above, was conducted entirely at the University of Connecticut and was completed more than a year before he accepted his position at Regeneron.<br />
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[5]. Elife. 2019 Jan 30;8:e43173. doi: 10.7554/eLife.43173.<br />
Comment on 'Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity'.<br />
Pacifici M(1), Shore EM(2).<br />
Author information: (1)Translational Research Program in Pediatric Orthopaedics, The Children's Hospital of Philadelphia, Philadelphia, United States. (2)Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, United States.<br />
DOI: 10.7554/eLife.43173 PMCID: PMC6353590 PMID: 30698141
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