Novel Therapeutic Small Molecule Strategy Targeting Bone Morphogenetic Protein Signaling to Prevent Upper Extremity Heterotopic Ossification
Abstract
Over 60% of wounded warriors injured by explosive devices or burns will develop heterotopic ossification (HO), the pathologic formation of mature bone in soft tissues such as muscle, tendon, or even joint spaces. HO presents a significant barrier to quality of life, by delaying rehabilitation and causing chronic pain, open wounds, and joint immobility and contractures. Patients with traumatic burn injuries are at particular risk of developing upper extremity HO severely limiting their functional and vocational abilities. Patients who present with radiographic evidence of HO often undergo surgical excision, which yields dissatisfying results due to incomplete resection, a high risk of recurrence, and an inability to restore range of motion, or improve chronic pain. Drugs which exist can cause adverse healing effects in trauma patients, require long-term treatment, and are unable to be implemented in patients with the highest risk only. Thus, a need exists to prevent HO using therapeutics and minimize treatment duration to avoid adverse effects. The central goal of this grant was to inhibit the noncanonical(TAK1) and canonical (ALK2) bone morphogenetic (BMP) signaling pathways, two synergistic pathways critical for mesenchymal condensation and cartilage formation to prevent or eliminate HO and mitigate joint contractures. We demonstrated the ability of these therapeutics to mitigate HO in our proven animal trauma models. Our overall goal was to generate a paradigm shift in our approach to patients at risk for HO, from delayed surgical excision or long-term treatment with non-specific inhibitors, to early preventative strategies which target high risk individuals with synergistic therapeutics. Having validated the efficacy of these treatments in animal models and cell lines, we believe the next step is to translate these to clinical studies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2019
- Accession Number
- AD1097059
Entities
People
- Benjamin Lévi
Organizations
- Board of Regents of the University of Michigan