Kyoto University researchers have successfully used a drug to regenerate new whole teeth in mice. The novel therapeutic approach, which uses antibodies, blocks the action of a gene known to regulate the growth of excess teeth. The engineered antibody is earmarked as a new treatment for missing teeth due to a genetic disorder known as tooth agenesis.

Tooth agenesis is a congenital disorder characterized by the absence of one or more teeth. It has three classifications dependent on the amount of missing dentition. For instance, where all teeth are absent the diagnosis of Anodontia is given. Where 1-5 teeth are missing hypodontia is diagnosed, and oligodontia is the name given for the absence of six or more teeth. Historically, the only way to treat tooth agenesis is with dental implants, braces to close the spaces, or dentures – with no therapeutic option available.

Harnessing genes to regrow teeth

Now, a study from researchers led by Kyoto University develops an antibody that blocks one specific gene to stimulate tooth growth in mice suffering from tooth agenesis. The team states their study is the first to use an antibody to successfully grow whole teeth – providing a whole new treatment option for this condition. The opensource study is published in the journal Science Advances.

It has long been established that the typical adult mouth contains 32 teeth. However, roughly 1 percent of the population possesses more or fewer teeth due to various genetic mutations. Presently, conditions causing a decrease in the normal number of teeth are called tooth agenesis. While conditions causing an increase of dentition in the oral cavity are called supernumerary teeth. It makes sense then that scientists have explored the genetic causes for having supernumerary teeth in adults in the hope they can tweak these genes to regrow missing teeth for those suffering from tooth agenesis.

To this end, it has been confirmed that the growth and structure of individual teeth depend on the interactions of several signaling molecules, including Bone Morphogenetic Protein (BMP) and the Wnt pathway. Nonetheless, as they both modulate the growth of multiple organs and tissues, drugs that directly affect their activity are avoided. This is because side effects could affect the entire body – meaning a highly targeted approach is needed here.

Recent studies from the group showed that Uterine Sensitization–Associated gene-1 (USAG-1) deficiency leads to enhanced BMP signaling, which, in turn, causes the growth of supernumerary teeth. This has led to the hypothesis that USAG-1 plays a key regulatory role in suppressing tooth development. And conversely, anything interfering with the binding of USAG-1 to BMP could accelerate tooth development.

A drug to regenerate missing teeth

Thus, the current trial investigates the effects of several special antibodies engineered to bind to USAG-1. It is in this way it can block the action of the gene on tooth development. The experiments will also determine whether BMP or Wnt signaling is dominant during tooth development.

In the current study, it was observed that USAG-1 controls the number of teeth by inhibiting the development of potential tooth germs in mice missing teeth. To hamper this, a monoclonal antibody was administered to mice suffering from congenital tooth agenesis which successfully regenerated their missing teeth. Interestingly, it was noted that the USAG-1–neutralizing antibody produces a whole tooth similar to supernumerary teeth seen in ferrets.

Regarding whether BMP or Wnt signaling is dominant during tooth development – several of the antibodies trialed greatly affected the whole body growth and survival rates of mice. As aforementioned, this is because both BMP and Wnt are involved in every aspect of embryonic development; making it difficult to discern which molecule the antibody needed to stop USAG-1 from interacting with. In spite of this fact, one antibody was identified that only disrupted the interaction of USAG-1 with BMP specifically to produce teeth.

These data suggest that BMP signaling is essential for determining the number of teeth in mice. Moreover, a single administration of the salient antibody was enough to generate a whole tooth – with subsequent experiments exhibiting the same benefits in ferrets.

The team surmises that using an antibody to block USAG-1 function relieves congenital tooth agenesis caused by various genetic abnormalities in mice. For the future, the researchers state they now plan to test the antibodies on other animals such as pigs and dogs.

Source: Kyoto University

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