EZH inhibitors as endoprosthetic device coatings that induce osteogenesis and promote implant osseointegration

Project Summary Abstract 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 EZH 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 EZH inhibitors stimulate bone formation by decreasing epigenetic inhibition of the Wnt catenin signaling pathway The research described in the current proposal will demonstrate that EZH 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 EZH inhibitors at the device tissue interface will minimize systemic exposure and toxicity specifically myelosuppression observed for EZH inhibitors currently in development for the treatment of cancer The project leverages the complementary knowledge and capabilities of Numerate Inc and Dr van Wijnen s laboratory Dr van Wijnen has extensively characterized the effects of EZH inhibition on bone formation and has significant experience with assays that assess growth and integration of MSCs with titanium device substrates Numerate s 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 EZH inhibitors for use in coated orthopedic implants 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 EZH Local release of the drug at the implant tissue interface will avoid the risk of myelosuppression observed with systemic exposure to EZH inhibiting anti cancer agents