Novel therapy to prevent alveolar bone loss in severe periodontitis

Novel therapy to prevent alveolar bone loss in severe periodontitis Abstract Periodontal disease affects almost half of US adults 30-years and older. More advanced disease, periodontitis, leads to retraction of the gums from the teeth, with loss of alveolar bone, and ultimately loss of teeth. A key step in progression of periodontitis involves the loss of alveolar bone that provides the underlying

support for the tooth. This process is mediated by bone-degrading osteoclasts (OC). Osteoclast activation by inflammatory mediators disrupts bone homeostasis, leading to loss of bone mass. OC differentiation from OC progenitor cells (OCP) is modulated by a cascade of integrated signaling culminating in stimulation by RANKL

that ultimately leads to fusion of OCP to form the active, multinucleated OC. While multiple fusogens, including the dendritic cell-specific transmembrane protein (DC-STAMP) and CD9, are recognized, recent data suggest a pivotal role for OC-stimulatory transmembrane protein (OC-STAMP). OC-STAMP knock-out mice exhibit

diminished alveolar bone loss in a standard ligature-induced model of periodontitis. Unlike anti-DC-STAMP, anti- OC-STAMP down-regulates expression of CD9. These studies of osteoclastogenesis involving OC-STAMP suggest a potential therapeutic intervention for periodontitis using an anti-OC-STAMP monoclonal antibody.

Proof-of-concept work utilized a murine-specific anti-OC-STAMP murine monoclonal antibody. During this Phase 1 project, we will identify and evaluate a panel of human anti-human OC-STAMP monoclonal antibodies. A lead antibody will be identified using a ligature-induced periodontitis model in a human OC-STAMP knock-in mouse

model. This work will produce a novel therapeutic to slow or even potentially halt loss of alveolar bone and teeth in severe periodontitis.