Japan pharma startup developing world-first drug to grow new teeth / Sep 24, 2023
“A team of scientists led by a Japanese pharmaceutical startup has been working on a drug to stimulate the growth of new teeth in what would be a world-first, aiming to put it on the market by around 2030. Toregem Biopharma, funded by Kyoto University, is expected to begin clinical trials on healthy adults in around July 2024 to confirm the drug’s safety, after the team succeeded in growing new teeth in mice in 2018. Most people have “tooth buds” that have the potential to become a new tooth, in addition to baby and permanent teeth, although the buds usually do not develop and subsequently disappear.
The team created an antibody drug that inhibits the protein that suppresses the growth of teeth.The drug works on these buds and stimulates their growth. In 2018, the team also administered the drug to ferrets, which have both baby and permanent teeth similar to humans, and new teeth grew. The team plans to hold a clinical trial for the drug from 2025 for children between 2 and 6 years old with anodontia, who are born without some or all permanent teeth. The children will be injected with one dose to induce teeth growth.
There are also hopes to utilize the drug in the future for adults who have lost teeth due to cavities. “Missing teeth in a child can affect the development of their jaw bone,” said Katsu Takahashi, co-founder of Toregem Biopharma and head of dentistry and oral surgery at Kitano Hospital in Osaka. “We hope the drug will serve as a key to solving those problems,” he said.”
ANTIBODY-BASED TOOTH REGENERATION
“A new study by scientists at Kyoto University and the University of Fukui, however, may offer some hope. The team reports that an antibody for one gene — uterine sensitization associated gene-1 or USAG-1 — can stimulate tooth growth in mice suffering from tooth agenesis, a congenital condition. The paper was published in Science Advances. Although the normal adult mouth has 32 teeth, about 1% of the population has more or fewer due to congenital conditions. Scientists have explored the genetic causes for cases having too many teeth as clues for regenerating teeth in adults.
According to Katsu Takahashi, one of the lead authors of the study and a senior lecturer at the Kyoto University Graduate School of Medicine, the fundamental molecules responsible for tooth development have already been identified. “The morphogenesis of individual teeth depends on the interactions of several molecules including BMP, or bone morphogenetic protein, and Wnt signaling,” says Takahashi. BMP and Wnt are involved in much more than tooth development. They modulate the growth of multiple organs and tissues well before the human body is even the size of a raisin. Consequently, drugs that directly affect their activity are commonly avoided, since side effects could affect the entire body.
Guessing that targeting the factors that antagonize BMP and Wnt specifically in tooth development could be safer, the team considered the gene USAG-1. “We knew that suppressing USAG-1 benefits tooth growth. What we did not know was whether it would be enough,” adds Takahashi. The scientists therefore investigated the effects of several monoclonal antibodies for USAG-1. Monoclonal antibodies are commonly used to treat cancers, arthritis, and vaccine development. USAG-1 interacts with both BMP and Wnt. As a result, several of the antibodies led to poor birth and survival rates of the mice, affirming the importance of both BMP and Wnt on whole body growth. One promising antibody, however, disrupted the interaction of USAG-1 with BMP only. Experiments with this antibody revealed that BMP signaling is essential for determining the number of teeth in mice. Moreover, a single administration was enough to generate a whole tooth.
Subsequent experiments showed the same benefits in ferrets. “Ferrets are diphyodont animals with similar dental patterns to humans. Our next plan is to test the antibodies on other animals such as pigs and dogs,” explains Takahashi. The study is the first to show the benefits of monoclonal antibodies on tooth regeneration and provides a new therapeutic framework for a clinical problem that can currently only be resolved with implants and other artificial measures. “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,” concludes Manabu Sugai of the University of Fukui, another author of the study.”
A. Murashima-Suginami, H. Kiso, Y. Tokita, E. Mihara, Y. Nambu, R. Uozumi, Y. Tabata, K. Bessho, J. Takagi, M. Sugai and K. Takahashi (2021). Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling. Science Advances, 7(7):eabf1798.
NEUTRALIZING ANTIBODY MEDECINE
World’s 1st drug to regrow teeth enters clinical trials
by Michelle Butterfield / September 25, 2023
“The ability to regrow your own teeth could be just around the corner. A team of scientists, led by a Japanese pharmaceutical startup, are getting set to start human trials on a new drug that has successfully grown new teeth in animal test subjects. Toregem Biopharma is slated to begin clinical trials in July of next year after it succeeded growing new teeth in mice five years ago, the Japan Times reports. Dr. Katsu Takahashi, a lead researcher on the project and head of the dentistry and oral surgery department at the Medical Research Institute Kitano Hospital, says “the idea of growing new teeth is every dentist’s dream. I’ve been working on this since I was a graduate student,” he told Japan’s national daily news site, the Mainichi, earlier this year. “I was confident I’d be able to make it happen.” In his research, which he’s been conducting at Kyoto University since 2005, Takahashi learned of a particular gene in mice that affects the growth of their teeth.
The antibody for this gene, USAG-1, can help stimulate tooth growth if it is suppressed – and scientists have since worked to develop a “neutralizing antibody medicine” that is able to block USAG-1. Now, his team has been testing the theory that “blocking” this protein could grow more teeth. After their successful tests on mice, the team went on to perform similarly positive trials on ferrets – animals who have a similar dental pattern to humans. Now, testing will turn to healthy adult humans and, if all goes well, the team plans to hold a clinical trial for the drug from 2025 for children between two and six years old with anodontia – a rare genetic disorder that results in the absence of six or more baby and/or adult teeth. According to the Japan Times, the children involved in the clinical trial will be injected with one dose of the drug to see if it induces teeth growth. If successful, the medicine could be available for regulatory approval by 2030. Takahashi hopes the new medicine could be just another option for those who don’t have a full set of teeth. “In any case, we’re hoping to see a time when tooth-regrowth medicine is a third choice alongside dentures and implants,” Takahashi told Mainichi.”
“new tooth is growing in a mouse treated with the tooth regrowth medicine”
THIRD GENERATION TEETH
World’s 1st ‘tooth regrowth’ medicine moves toward clinical trials in Japan / June 12, 2023
“A Japanese research team is making progress on the development of a groundbreaking medication that may allow people to grow new teeth, with clinical trials set to begin in July 2024. The tooth regrowth medicine is intended for people who lack a full set of adult teeth due to congenital factors. The team is aiming to have it ready for general use in 2030. In prior animal experiments, the medicine prompted the growth of “third-generation” teeth following baby teeth and then permanent adult teeth. “The idea of growing new teeth is every dentist’s dream. I’ve been working on this since I was a graduate student. I was confident I’d be able to make it happen,” said Katsu Takahashi, lead researcher and head of the dentistry and oral surgery department at the Medical Research Institute Kitano Hospital in the city of Osaka.
Anodontia is a congenital condition that causes the growth of fewer than a full set of teeth, present in around 1% of the population. Genetic factors are thought to be the major cause for the one-tenth of anodontia patients who lack six or more teeth, a condition categorized as oligodontia. These conditions are also known as tooth agenesis. People who grow up with tooth agenesis struggle with basic abilities like chewing, swallowing and speaking from a young age, which can negatively impact their development. After completing a dentistry degree, Takahashi went on to graduate studies in molecular biology at Kyoto University in 1991. Afterwards, he studied in the U.S. Around that time, research around the world had begun to pinpoint genes that, when deleted, would cause genetically modified mice to grow fewer teeth. “The number of teeth varied through the mutation of just one gene. If we make that the target of our research, there should be a way to change the number of teeth (people have),” Takahashi said of his thoughts at the time.
It was around 2005, when he delved further into the subject at Kyoto University after returning to Japan, that he began to see a bright path for his continued research. The researchers found that mice lacking a certain gene had an increased number of teeth. A protein called USAG-1, synthesized by the gene, was found to limit the growth of teeth. In other words, blocking the action of that protein could allow more teeth to grow. Takahashi’s research team narrowed their focus onto USAG-1, and developed a neutralizing antibody medicine able to block the protein’s function. In experiments in 2018, mice with a congenitally low number of teeth were given medicine that resulted in new teeth coming through. The research results were published in a U.S. scientific paper in 2021, and gained much attention as the beginnings of the world’s first tooth regeneration medicine.
Work is now underway to get the drug ready for human use. Once confirmed to have no ill effects on the human body, it will be aimed at treating children aged 2 to 6 who exhibit anodontia. “We hope to pave the way for the medicine’s clinical use,” Takahashi said. If successful, a drug to regenerate teeth may be a game-changer for the entire field of dentistry. Animals including sharks and some reptile species can continuously regrow teeth. It’s been assumed that humans only grow two sets of teeth in their lifetime, but in fact, there is evidence that we also have the “buds” for a third set. Around 1% of the population exhibits the converse of anodontia: hyperdontia, a congenital condition causing a higher-than-normal number of teeth. According to research by Takahashi’s team, one in three such cases manifests as the growth of a third set of teeth.
Takahashi believes that in most cases, humans’ ability to grow a third set was lost over time. When the researchers applied the drug to ferrets, they grew an additional seventh front tooth. As the new teeth grew in between the existing front teeth and were of the same shape, the medicine is thought to have induced the generation of third-set teeth in the animals. When treatment of teeth is no longer possible due to severe cavities or erosion of the dental sockets, known as pyorrhea, people lose them and need to rely on dental appliances such as dentures. The ability to grow third-generation teeth could change that. “In any case, we’re hoping to see a time when tooth-regrowth medicine is a third choice alongside dentures and implants,” Takahashi said.”
For further information or inquiries about Takahashi’s research, please visit https://kitano-hp.or.jp/toothreg/ (in Japanese).”
REPROGRAMMED STEM CELLS