Novel Therapeutic Small-Molecule Strategy Targeting Bone Morphogenetic Protein Signaling to Prevent Upper Extremity Heterotopic Ossification

Objectives and Rationale: This proposal is designed to address the Fiscal Year 2015 Peer Reviewed Orthopaedic Research Program Applied Research Award focus area of prevention of heterotopic ossification (HO) by providing a therapeutic strategy to prevent the development of post-traumatic HO as occurs in the upper extremity. HO is the pathologic formation of extra-skeletal bone within soft tissues that occurs in patients with severe trauma. This proposal has been developed to specifically address HO prevention and treatment in patients with severe trauma such as is seen with orthopaedic and blast-related injuries from improvised explosive devices and explosively formed projectiles that cause severe trauma to patients. The overall goal of this proposal is to target two synergistic pathways to prevent trauma-induced HO while minimizing treatment duration.

With dramatic improvements in survival from combat-related blast injuries, we have witnessed a concomitant increase in patients with debilitating injuries that drastically diminish quality of life. Of the nearly 15,000 battle injuries suffered in Operations Iraqi Freedom/New Dawn and Enduring Freedom, over 50% of those injuries were extremity injuries; an additional 5%-20% of the injuries were burn injuries. Of these wounded Soldiers with extremity injuries, over 60% of them will go on to develop HO, a severely debilitating disease process. HO also causes significant disability in hundreds of thousands of civilians and Veterans with upper extremity burn and orthopaedic injuries. For example, over 80% of patients with fractures and 100% of patients with revision joint replacements will develop HO. As a result of forming bone outside of the normal skeleton, HO leaves patients with severe chronic pain, open wounds, and limited range of motion.

Current treatment strategies address HO after its development with surgical excision. However, surgery is unable to restore range-of-motion, which has often been chronically limited due to HO, cannot address chronic pain, and causes prolonged wounds with poor healing. After excision, patients often develop recurrence within the original tissue bed, which necessitates re-excision, or continues to cause the original signs and symptoms. Though several medications have been previously tested, all have negative side effects and all fail to target the causative signaling mediators that lead to HO. We offer a paradigm shift in the prevention and management of HO, to inhibit two synergistic signaling pathways critical to HO, and optimally time these treatments to minimize duration and improve our precision with patient selection.

Potential Clinical Applications, Benefits, and Risks: This proposal is designed to be translatable and simulates the real-world trauma and management that patients may expect to receive. First, we use two clinically relevant models of trauma-induced HO, which are broadly applicable to combat-wounded military personnel and to civilians with significant trauma. Secondly, we utilize two novel inhibitors targeting different but synergistic pathways in the bone formation pathway; this method is highly translatable by accounting for multiple signaling mediators. Thirdly, this proposal addresses duration of treatment by selecting a short time period of treatment to minimize cost, improve adherence, and avoid adverse consequences. Finally, by using a novel imaging technique, this proposal addresses patient selection so that only those patients at the highest risk of developing HO are treated prior to fulminant HO formation. The combination of these techniques makes this proposal an important preclinical study that lends itself to establishing key data necessary to push forward definitive clinical trials.

Projected Timeline and Expected Patient-Related Outcomes: In this proposal, we plan to rapidly deploy our optimized treatment interventions. In the first 12 months, we will validate our therapeutic strategy to prevent HO in our trauma-induced HO models. In the last 12 months, we will determine the precise timing of administration and demonstrate whether immediate or delayed treatment is sufficient to inhibit HO. Upon completion of this proposal's aims, we will test these drugs on human HO cell lines and submit to an Institutional Review Board to begin a clinical trial studying these drugs in trauma patients in coordination with the Naval Medical Research Center and the University of Michigan.

Benefit to Service Members, Veterans, and/or Their Family Members: This proposed research will significantly improve current diagnostic and treatment strategies available to all patients who are at risk of developing HO. Through this proposal, we will improve our understanding of the role of novel bone morphogenetic protein signaling pathways that work synergistically to form HO. This proposal will lead to novel, targeted pharmacologic interventions to prevent HO in a highly directed and prec .......