A Novel Antibody Therapy to Rescue Congenital Teeth Defects

Tooth development is strictly regulated by crosstalk between multiple developmental signal transduction pathways. However, in certain congenital genetic conditions, this control is lost, which results in the under/over development of teeth, resulting in a decrease or increase in the number of teeth. Using mouse models, a team of scientists from Kyoto University and Fukui University, Japan, have demonstrated an approach for tooth regeneration.

USAG-1 (encoded by uterine sensitization associated gene-1) has been identified as a protein that interacts with BMP (Bone Morphogenetic Protein) and Wnt pathway. The knockout model of Usag-1 showed an acceleration of tooth formation via BMP-mediated tooth morphogenetic and Wnt-mediated supernumerary teeth. Combining the Usag-1 knockout model with a mouse model of the undeveloped tooth, the authors of the report, published in Science Advances, investigate how USAG-1 controls the interplay between BMP and Wnt to promote tooth formation.

USAG-1’s Role in Tooth Formation

Deleting Usag-1 in a mouse model with arrested tooth development could rescue early tooth formation and promote tooth morphogenesis. Hence, the team generated monoclonal antibodies against USAG-1 protein and characterized them for their ability to bind USAG-1 interactors-BMP and Wnt in vitro. When these neutralizing antibodies were injected into pregnant mice with tooth agenesis, the offspring had rescued phenotypes in a dose-dependent manner, ranging from reversed hypodontia to supernumerary teeth.

The antibodies inactivated BMP signaling in vitro, suggesting that the rescue was regulated via BMP. Furthermore, the team identified the epitope of USAG-1 as important for BMP binding by epitope mapping and NMR ( Nuclear Magnetic Resonance). They also identified epitopes necessary to bind the Wnt receptor, LRP6. However, the antibodies did not inhibit USAG-1 binding to LRP6 to the extent comparable to BMP inhibition, suggesting that BMP signaling is more crucial in recovering tooth development. With a single systemic injection of anti-USAG-1, there was the efficient formation of a whole tooth, indicating recovery of congenital tooth defects.

The authors note that Wnt signaling may contribute minimally to the tooth regeneration but may not be excluded and needs further studies. Conversely, USAG-1 mediated BMP activation may not cure all congenital tooth defects, but only those that have a genetic linkage to Usag-1, indicating the need for further clinical trials and selection of patients based on biomarkers. However, the neutralizing antibody against USAG-1 holds promise as a targeted therapy for tooth regeneration.

Since dental solutions to congenital agenesis are restricted to expensive implants and other artificial devices, this study explores the possibility of a therapeutic framework of monoclonal antibodies. “Conventional tissue engineering is not suitable for tooth regeneration. Our study shows that cell-free molecular therapy is effective for a wide range of congenital tooth agenesis,” concluded Manabu Sugai of the University of Fukui, one of the lead authors of the study.

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Author

Sahana Shankar

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