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Preventative Therapeutics for Heterotopic Ossification

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Technical Report,30 Sep 2014,29 Sep 2015

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The Childrens Hospital of Philadelphia Philadelphia United States

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HO consists of formation of ectopic bone within muscles, connective tissues and blood vessels and can cause loss of normal posture and mobility, chronic pain, prosthesis fitting problems, deep venous thrombosis or other problems. HO is induced by trauma, burns and invasive surgeries and is thus very common amongst our severely wounded service-members. HO has in fact emerged as the single most important barrier to functional activity and return-to-duty in recent analyses. Current treatments are not wholly effective, are fraught with complications and may actually trigger additional HO in certain circumstances. Clearly there is an urgent need to create new, effective, specific and easy-to-deliver therapies for HO. HO closely resembles the process by which endochondral bones normally form and grow during prenatal and postnatal life. Because that process requires a steep drop in activity of nuclear retinoic acid receptors RARs, we hypothesized that acute pharmacological reactivation of the RARs could block HO. In previous studies sponsored by the USAMRMC, we did find that synthetic selective RAR agonists are potent inhibitors of surgery-induced HO in mice. One of the most effective RAR agonists we tested was R667 Palovarotenepreviously used in an FDA-approved Phase 2 trial. R667 is thus our lead compound at present.

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