Preventative Therapeutics for Heterotopic Ossification
Annual rept. 30 Sep 2013-29 Sep 2014
CHILDREN'S HOSPITAL OF PHILADELPHIA PA
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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 and 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 studies by DOD researchers and physicians. 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. The formation of HO lesions 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 re-activation of the RARs could block HO. In previous studies sponsored by the USAMRMC, we did in fact 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 Palovarotene previously used in an FDA-approved Phase 2 trial for another disease. R667 is thus our lead compound at present and will be used in additional HO animal models in this project.
- Anatomy and Physiology
- Medicine and Medical Research