With an aging population and increased life span, the number of patients requiring reconstructive joint surgeries or joint replacements continues to increase. Many patients undergoing arthroplasty procedures suffer from bone disorders such as osteoporosis, severe arthrosis or osteopenia, with a bony matrix that impedes firm anchoring of implants to existing bone. This results in poor implant osseointegration and aseptic loosening, and requires revision surgeries in many patients. The need and opportunity exists for new therapeutic strategies that improve bone-implant contact and device osseointegration. The objective of the proposed project is to discover small molecule inhibitors of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) that can be incorporated in the surface coating of a model titanium device substrate. Upon release from the substrate, these compounds will stimulate osteogenic differentiation of mesenchymal stem cells (MSCs) at the device/tissue interface, promoting bone growth and device osseointegration. Dr. Andre van Wijnen of Mayo Clinic and others have demonstrated that EZH2 inhibitors stimulate bone formation by decreasing epigenetic inhibition of the Wnt/?-catenin signaling pathway. The research described in the current proposal will demonstrate that EZH2 inhibitors, when incorporated into hydroxyapatite surface coatings of titanium disks, will enhance osteogenic differentiation of human MSCs cultured on the disks as measured by relevant biomarkers and immunohistochemical staining. Successful completion of this Phase I SBIR feasibility study will form the basis for a program directed at the development of a drug/device combination product that will greatly enhance implant osseointegration, reduce the need for revision surgeries, and be convenient and cost effective with respect to manufacturing and preparations required by surgical staff. Relative to orally or parenterally administered compounds, local delivery of bone pro-anabolic EZH2 inhibitors at the device/tissue interface will minimize systemic exposure and toxicity, specifically myelosuppression observed for EZH2 inhibitors currently in development for the treatment of cancer. The project leverages the complementary knowledge and capabilities of Numerate, Inc. and Dr. van Wijnens laboratory. Dr. van Wijnen has extensively characterized the effects of EZH2 inhibition on bone formation, and has significant experience with assays that assess growth and integration of MSCs with titanium device substrates. Numerates team is experienced in small molecule drug discovery and development, and will apply its ligand-based, AI-driven small molecule drug design platform to the design and optimization of EZH2 inhibitors for use in coated orthopedic implants.
Public Health Relevance Statement: Narrative The objective of the proposed project is to develop a small molecule drug that enhances the osseointegration of coated orthopedic implants in patients suffering from osteoporosis, severe arthrosis or osteopenia. When released from the implant coating, this drug will promote osteogenic differentiation of mesenchymal stem cells and stimulate maturation of pre-committed osteoblasts local to the implant by inhibiting the epigenetic modification enzyme EZH2. Local release of the drug at the implant/tissue interface will avoid the risk of myelosuppression observed with systemic exposure to EZH2-inhibiting anti-cancer agents.
Project Terms: Acidity; Adipocytes; Adipose tissue; aging population; alkalinity; analog; Antineoplastic Agents; base; beta catenin; Biochemical; Biological Assay; Biological Markers; Biomimetics; Blood Vessels; bone; Bone Diseases; Bone Growth; Bone Matrix; cancer therapy; Catalytic Domain; Chondrocytes; Clinic; Complex; cost effective; Cultured Cells; Dental Implants; design; Development; Devices; Dimensions; drug candidate; Drug Design; drug discovery; Enhancers; Enzymes; Epigenetic Process; experience; Exposure to; EZH2 gene; Feasibility Studies; Fracture Healing; Genes; Goals; Growth; histone methyltransferase; Homologous Gene; Human; Hydroxyapatites; Impairment; Implant; implant coating; improved; In Vitro; in vivo; inhibitor/antagonist; interest; Joint repair; Kinetics; knock-down; Knowledge; Laboratories; Lead; Ligands; Limb structure; Longevity; Measures; Mesenchymal Differentiation; Mesenchymal Stem Cells; Modeling; Modification; Myelosuppression; novel; novel therapeutic intervention; Operative Surgical Procedures; Oral; Orthopedics; Osseointegration; Osteoblasts; Osteogenesis; osteogenic; Osteopenia; Osteoporosis; osteosarcoma; Patients; Penetration; Pharmaceutical Preparations; Phase; Play; Polycomb; Precipitation; Preparation; prevent; Procedures; programs; Property; Replacement Arthroplasty; Research; Research Project Grants; Risk; Safety; scaffold; Signal Pathway; Signal Transduction; Skeletal Development; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; Solubility; Staining method; Stains; Stromal Cells; surface coating; Therapeutic; Tissues; Titanium; Toxic effect; Work
