Because bony defects have limited regenerative capability, the importance of bone grafting during reconstructive surgery for craniomaxilofacial trauma and congenital craniofacial anomalies is widely recognized. To avoid the morbidity associated with autologous bone graft harvest, application of osteoinductive molecules such as the bone morphogenetic proteins (BMPs) has been intensively studied. We have identified a novel osteoinductive molecule that is directly regulated by core-binding factor a1, a critical mediator of osteoblast formation and function. Molecule overexpression in vitro significantly increased osteoblast differentiation and mineralization, while overexpression in vivo significantly increased premature bone formation in the calvarial sutures of transgenic animals. Pilot studies comparing the novel molecule to an equivalent dose of BMP2 demonstrated comparable levels of bone regeneration in a rat calvarial defect model. Interestingly, our in vitro data also suggest an additive or synergistic effect between the novel molecule and BMP2 on induction of alkaline phosphatase activity. To determine if this molecule can feasibly replacement or complement existing osteoinductive molecules such as BMPs, we propose this Phase I study to: 1) confirm molecule efficacy in bone regeneration; 2) determine optimal dosages for bone regeneration using the molecule, BMP2, or BMP7 in a rat calvarial critical size defect model; 3) compare optimized dosages in the calvarial defect model; and 4) evaluate the efficacy of a commercial osteoconductive carrier combined with our molecule in bone regeneration. Phase I completion will allow analyses of the molecule's osteoinductive capacity against a BMP benchmark within a specific ceramic carrier. Phase II studies will focus on further molecule development in two distinct areas of BMP replacement therapy and BMP adjunct therapy and provide the foundation for eventual product commercialization. Our long term goal is to develop an effective autograft bone substitute.
