Researchers from Kitano Hospital and Kyoto University in Japan have been developing a drug that deactivates a gene called USAG-1 to treat tooth loss and regrow teeth. Their research undertaking has also led to the creation of the startup venture Toregem Biopharma in March 2020 which aims to commercialize this treatment option in the future. Nonetheless, beginning in the fourth quarter of 2024, the researchers have expanded their testing to human participants. A potential drug for regrowing teeth might be on its way.
Explaining the Science Behind USAG-1 Gene Targetting: A Monoclonal Antibody Drug For Regrowing Teeth
Background
A team of researchers led by Katsu Takahashi, head of the dentistry and oral surgery department at Kitano Hospital, has been studying the possibility of developing a drug that can treat children with a rare genetic condition called anodontia which prevents teeth growth in infancy. The same drug is also aimed to target adults with tooth loss.
Congenital tooth agenesis or the failure to develop teeth affects about 0.1 percent of the population and about 10 percent of children suffer from partial tooth loss. Adults also suffer from tooth loss due to several causes like gum diseases, tooth decay, and physical trauma. Note that humans and most other mammals only grow two sets of teeth.
The current available options for addressing tooth loss are dentures and dental implants. However, in a research undertaking that has spanned more than two decades, researchers have identified a gene that affects normal tooth development. This is the USAG-1. Takashi and his team have set their eyes on this specific research on this gene.
USAG-1 or uterine sensitization-associated gene-1 is expressed in the kidneys and the teeth. It has relevant roles in different biological processes. For example, because it influences thymocytes or T cell immune response, it has been a target for improving treatment options concerning autoimmune nephropathy and antibody-mediated rejection.
The expression of USAG-1 influences tooth development. It controls the number of teeth and prevents the development of potential tooth germs by regulating Wnt signaling and blocking bone morphogenetic protein signaling. Both are crucial in tooth development. This role has prompted researchers to explore its relevance in congenital tooth agenesis.
Research
An earlier study published in 2021 used USAG-1-specific small interfering RNA in a mouse model to suppress USAG-1 expression locally. The goal was to reverse the effects of Runx2 deficiency. Note that the absence of this gene halts tooth germ development in mice. Results showed restoration of tooth formation in deficient mandibles.
Further studies identified an antibody that targets the USAG-1 gene. Findings from specific research published in 2021 showed that this antibody had demonstrated promise in regenerating teeth in mice by enhancing bone morphogenetic protein signaling. The study concluded that this could pave the way for similar treatments in humans.
Another study published in 2023 built on the previous ones. It confirmed that blocking USAG-1 activates bone morphogenetic protein signaling and results in the development of supernumerary or extra teeth. It also confirms that blocking this gene with antibodies shows promise as a tooth regeneration therapy for normal or genetic tooth loss.
Implications
The team of Takahashi anchored their specific research undertaking on the idea of developing an antibody to block USAG-1 expression and promote teeth regeneration. The resulting drug is aimed primarily at children with congenital tooth agenesis. However, based on previous findings, it can also be used to treat tooth loss in adults due to certain conditions.
Previous studies essentially suggest that inactivating USAG-1 can not only improve congenital tooth agenesis but also promote late-stage tooth morphogenesis and activate third dentition. The proposed monoclonal antibody drug is basically aimed at treating tooth loss and deformation due to genetics and promoting tooth regeneration in adults.
Takashi has been conducting experiments in mouse models since 2021 as part of the initial drug development process. However, beginning in October 2024, his team has entered clinical trials involving adult test subjects within the Kyoto University Hospital. Nevertheless, once results show both success and safety, they expect to commercialize it by 2030.
It is worth noting that an antibody drug that targets a protein nearly identical to USAG-1 is already being used to treat osteoporosis. The main point of these antibody-based treatments is to promote regenerative medicine by blocking or inhibiting processes or specific genes or proteins that render human bodies without regenerative capabilities.
The prospect is exciting. However, drug development is a strenuous process. Findings from the earlier animal models do not always apply to humans. The current phase involves adults. Phase two will involve children. Subsequent phases of the clinical trials will have to guarantee effectiveness and safety in consideration of broader applications.
FURTHER READINGS AND REFERENCES
- Mishima, S., Takahashi, K., Kiso, H., Murashima-Suginami, A., Tokita, Y., Jo, J.-I., Uozumi, R., Nambu, Y., Huang, B., Harada, H., Komori, T., Sugai, M., Tabata, Y., and Bessho, K. 2021. “Local Application of Usag-1 siRNA Can Promote Tooth Regeneration in Runx2-deficient Mice. Scientific Reports. 11(1). Springer Science and Business Media LLC. DOI: 1038/s41598-021-93256-y
- Murashima-Suginami, A., Kiso, H., Tokita, Y., Mihara, E., Nambu, Y., Uozumi, R., Tabata, Y., Bessho, K., Takagi, J., Sugai, M., and Takahashi, K. 2021. “Anti–USAG-1 Therapy for Tooth Regeneration Through Enhanced BMP Signaling.” Science Advances. 7(7). American Association for the Advancement of Science. DOI: 1126/sciadv.abf1798
- Ravi, V., Murashima-Suginami, A., Kiso, H., Tokita, Y., Huang, C. L., Bessho, K., Takagi, J., Sugai, M., Tabata, Y., and Takahashi, K. 2023. “Advances in Tooth Agenesis and Tooth Regeneration.” Regenerative Therapy. 22(160-168). Elsevier BV. DOI: 1016/j.reth.2023.01.004