Preventative Therapeutics for Heterotopic Ossification

Objectives and Rationale for the Application: In this project, we study heterotopic ossification (HO) and are testing therapies to cure it. HO consists of formation of extra bone within the muscles, near tendons and ligaments, inside the blood vessels, and other places in the body. HO is triggered by trauma, burns, nerve damage, immobilization, and other conditions, and can also occur in patients undergoing large surgeries such as hip or knee replacement. Because trauma, burns, and other severe wounds are regrettably common in our soldiers in the current war theaters and conflicts, HO often affects and afflicts many of them. The consequences of having HO are not minor. Patients with HO can experience loss of normal posture and movement, chronic pain, prosthesis fitting problems, formation of pressure ulcers, deep venous thrombosis, and other health problems. Indeed, HO has emerged as the single most important barrier to functional activity and return-to-duty in a recent analysis of wounded active duty service-members. Current treatments are not wholly effective, have side effects, and are not directed specifically against HO. Surgery is often used to remove the HO lesions, but the procedure is traumatic, and it can actually trigger additional HO. Surgery is not recommended for patients in the general population who suffer from recurrent, congenital, severe, and often fatal forms of HO (seen in adults as well as children). Clearly, there is a very urgent need to create new, effective, specific, and easy-to-deliver therapies for HO, a debilitating disease that is hampering the return to productive life and military service and also affects a considerable portion of civilian patients and children. In previous studies we conducted under the auspices of the Department of Defense, we discovered that drugs called retinoids are very potent inhibitors of HO in animal models of the disease. Before this new and extremely promising therapy can be used on wounded soldiers and civilian patients, we must carry out additional studies in animals to make sure that the therapy is as safe as it appears to be, is effective after combat injury situations (such as those occurring after a blast), and could be delivered easily by mouth or injection.

Ultimate Applicability of the Research: Types of Patients: As pointed out above, the therapy would be beneficial to various patient groups suffering from diverse forms of HO. Severely wounded soldiers could be given the treatment immediately after injury or even after 4 to 6 days (our studies show that the therapy is still effective). It could be given to patients undergoing large invasive surgeries, before or after surgery. Last, but not least, it could be given to children suffering from congenital forms of HO that are extremely severe and almost always fatal and for which there are no treatments at the moment.

Potential Benefits and Risks: The benefits of this new therapy would be major and significant because there are no effective means to prevent HO in a definitive manner at present. As with any other pharmacologic treatment, there are potential risks. The drugs appear safe at the moment. One of them (called palovarotene) was previously tested for a chronic disease in a Phase 2 Food and Drug Administration (FDA)-approved clinical trial and was given to patients every day for 2 years. In the case of HO, our studies indicate that the drug will be given for 2 to 3 weeks only. In sum, we expect the treatment to be safe for HO patients, but we need to make sure of this.

Projected Time to Achieve Clinical Relevant Outcome: We expect to be in a position to prepare an application to the FDA for a Phase 2 HO clinical trial soon after we complete the present 3-year project. At that point, we will have comprehensive data on safety and effectiveness in various HO animal models (large and small animals as required). In addition, because palovarotene was already tested in a Phase 2 trial previously, this precedent should greatly facilitate our task to receive approval and implement a clinical trial for HO.

Benefits to Military Populations and Combat-Related Orthopaedic Research: As stressed above, HO has emerged as the single most important barrier to functional activity and return-to-duty in a recent analysis of wounded active duty service-members. This analysis was conducted by a team of physicians at the Naval Medical Research Center and included Dr. J. Forsberg (who serves as one of the two Principal Investigators in this project). Given its potency and specificity, the drug-based therapy studied here will represent a new therapeutic tool to be used soon after battlefield injury and should be equally effective in cases of recurrent HO seen in both soldiers and civilians. The project will also benefit combat-related orthopaedic research because the studies will test HO in a blast-injury animal model and its collateral problems, including wound healing and fracture .......