Grants Funded

Abstract
Over 60% of major burns, 65% of combat injuries and 20% of pressure ulcer and joint surgery patients will develop heterotopic ossification (HO), the deposition of bone in soft tissues, such as muscle, tendon or fascia. Current treatment involves surgical excision; however, even after excision, >75% of patients have restricted range of motion and residual pain. Barriers to improved outcomes in HO patients include a lack of understanding of the timing of key signaling mechanisms that lead to the development of HO and targeted therapeutics with minimal off target toxicity. Through this proposal, we plan to improve our understanding of the signaling mechanisms which lead to HO, and to prevent HO through optimally timed inhibition of bone morphogenetic protein (BMP) ligand. Specifically, we will define the time course of key signaling mediators of HO and deploy a potent BMP ligand trap (Alk3-Fc) to prevent HO formation with administration during timed therapeutic windows.
Aim 1: To define and characterize the time course of HO mediators that can be targeted therapeutically. Our preliminary studies using the burn/tenotomy mouse model have shown that HO progresses through a series of identifiable stages including an initial phase of mesenchymal cell recruitment and proliferation, followed by cartilage formation and finally ossification. We hypothesize that each phase will be distinguishable on the basis of expression of critical signaling mediators. Identification of the signaling mediators present during each of these phases will provide a roadmap to guide therapy administration based on the critical timing of the targeted mediator.
Aim 2: To prevent HO using continuous treatment or abbreviated, directed treatment with a novel Alk3-fc BMP ligand trap. Our recent studies have demonstrated that BMP receptor kinase inhibition significantly diminishes HO. However, therapeutics targeting kinase receptors result in substantial off-target effects due to non-specific activity. Therefore, we will use a novel therapeutic agent, Alk3-fc, which serves as a BMP ligand trap by mimicking the ligand binding region of the BMP type I receptor Alk3. Animals will receive treatment daily, either long-term (6 weeks) or during timed therapeutic windows based on our knowledge of the histologic phases of HO (weeks 0-2, weeks 2-4, weeks 4-6) in addition to no treatment controls. Toxicity will be monitored by assessment of wound healing and osteopenia.

Biography
Benjamin Levi, MD has been involved in Burn research since High School when given the opportunity to work in the Burn Laboratory of Richard Gamelli MD and Luisa DiPietro DDS, PhD. Subsequently, and for three consecutive summers, he worked in the Burn and Shock Trauma laboratory of Dr. Gamelli and Dr. Luisa DiPietro with a focus on wound healing and inflammation. Dr. Levi completed his undergraduate education at Washington University where he graduated Phi Beta Kappa in Biology and Spanish. He then attended medical school at Northwestern University and subsequently completed his Plastic and Reconstructive Surgery residency at the University of Michigan. During his residency he completed a 2 year post-doctoral research fellowship at Stanford University while funded by a NIH Ruth L. Kirschstein National Research Service Award. His research focused on basic bone biology, bone development, stem cell biology and tissue engineering. After his residency and research training, he took an additional year to be the Kidder Fellow in Burn Surgery and Surgical Critical Care at Massachusetts General Hospital and Shriner’s Hospital for Children in Boston. Dr. Levi is currently founder and director of the Burn/Wound and Regenerative Medicine Laboratory at the University of Michigan. This lab has focused on the significant clinical problem of heterotopic ossification. Specifically, Dr. Levi has developed new animal models to study this complex process and is working to improve early diagnostic and treatment modalities.