What if lost teeth could grow back naturally?
For centuries, tooth loss has been treated with artificial solutions such as dentures, bridges, or implants. But a new wave of research is shifting that approach. Instead of replacing missing teeth, scientists are exploring how to regrow them by tapping into the body’s own regenerative potential.
At the center of this research is uterine sensitization-associated gene-1 (USAG-1), a protein that suppresses tooth development by inhibiting two key pathways, Wnt and Bone Morphogenetic Protein (BMP). In preclinical studies in mice and ferrets, scientists from Kitano Hospital, along with other Japanese research institutions, discovered that blocking USAG-1 using antibodies triggered the natural formation of new teeth, and importantly, did so without major side effects.
Building on these results, scientists developed TRG-035, an experimental human monoclonal antibody designed to target USAG-1. The drug is now being tested as a potential therapeutic for conditions involving tooth loss and agenesis. In September 2024, Kyoto University Hospital launched the first human clinical trial of TRG-035, enrolling 30 adults with partial tooth loss. The Phase I clinical trial focuses primarily on safety, while also monitoring whether signs of tooth regeneration occur.
If safety and efficacy are confirmed in ongoing and future trials, TRG-035 could become the first drug capable of regenerating real, living teeth. This would mark a breakthrough in dentistry, providing a natural alternative to prosthetic solutions. Further trials will need to establish how durable regenerated teeth are, how safe the treatment remains long term, and how well it works across different patient groups.
The story of tooth regeneration
To understand how today’s advances became possible, it helps to revisit how teeth naturally form. Teeth begin as small structures called tooth buds, or tooth embryos. Baby (deciduous) teeth form first, followed by permanent teeth that push through the gums. Under normal circumstances, tooth growth ends here, leaving humans with only two sets of teeth for life.
A major breakthrough came in 2007, when Dr. Katsu Takahashi’s team discovered that mice lacking the gene USAG-1 developed extra teeth in areas where growth would normally stop. This revealed that USAG-1 functions as a biological brake on tooth formation. Removing that brake allowed dormant tooth germs to restart their growth.
Further studies explained how the mechanism works. USAG-1 is a secreted protein that suppresses BMP and interferes with Wnt signaling, both essential for initiating and shaping teeth. Without USAG-1, these pathways remain active, creating the conditions for new teeth to develop. This made USAG-1 a compelling target for therapies that aim to regenerate teeth naturally.
Researchers then shifted from genetic studies to experimental treatments. By blocking USAG-1 using antibodies or RNA interference, they successfully reactivated tooth growth in animal models. A 2021 study provided proof-of-concept that targeting USAG-1 could trigger regeneration directly from the body’s own tissues.
Redefining dental care with regenerative medicine
At the forefront of this breakthrough is Toregem Biopharma, a company founded in 2020 to bring Dr. Takahashi’s research on natural tooth regeneration into clinical reality. The company focuses on developing antibody-based drugs that stimulate natural tooth growth. Its team includes experts in dental medicine and pharmaceutical development, enabling the company to move discoveries from the laboratory into clinical use.
In 2022, Toregem formed a strategic partnership with WuXi Biologics, a global Contract Research, Development, and Manufacturing Organization (CRDMO), for the development and production of TRG-035.
Tooth Regeneration: Other Key Players
Our patent data shows that Kyoto University, the University of Fukui, and Osaka University are key players in tooth regeneration research. They often appear together on core patents related to USAG-1 neutralizing antibodies and RNA-based therapies. Much of this work is driven by the group of inventors led by Dr. Katsu Takahashi, together with Manabu Sugai, Yoshihito Tokita, Junichi Takagi, and Emiko Mihara, who helped establish USAG-1 as a target for growing new teeth.
Their work provided the genetic and molecular basis for growing new teeth and built the key patents behind TRG-035, helping drive early innovation in regenerative dentistry. Aichi Prefecture also appears as a co-assignee on several core patents, showing how regional government programs are backing regenerative medicine and helping sustain innovation in this field.
Independent inventor Bao Yang has applied for a nanoparticle-based dental healing preparation that combines an anti-USAG-1 antibody with traditional medicine components. This is detailed in patent CN120501888, titled “Frontal dental healing targeting nano preparation and preparation process thereof.” Meanwhile, U.S.-based SOHM has filed patents related to genome editing and biopharmaceutical approaches, as outlined in WO2025128981A1. These newer entrants highlight the growing diversity of strategies and the spread of interest beyond Japan.
Tooth Regeneration: Patenting Activity
Tooth regeneration patent activity began to surge in 2019, with three granted patents and eight priority filings. This early wave established USAG-1 inhibition as a treatment approach and laid the foundation for future innovations in the field.
Activity in later years has been more sustained, with several applications filed between 2020 and 2022, and only a few added from 2023 onward. These filings primarily build on the original claims by exploring variations in antibody formats, delivery methods, and therapeutic applications, rather than introducing entirely new directions. The absence of new grants after 2019 is expected, as approvals typically lag behind applications, and outcomes from the 2020–2022 cohort may still emerge in the coming years.
Tooth Regeneration: Top Technology Areas
Patent classifications provide a clear picture of where innovation in tooth regeneration is concentrated. The majority of filings fall under A61K (preparations for medical, dental, or cosmetic purposes) and A61P (therapeutic activity of compounds or preparations). Together, these codes confirm that most activity is directed toward drug formulations and their therapeutic uses, consistent with the development of antibody-based treatments such as TRG-035.
The next largest category is C07K (peptides, including antibodies), highlighting the central role of engineered proteins in modulating USAG-1. A smaller but notable share is seen in C12N (biotechnology), which captures filings related to genetic engineering, cell culture, and exosome production. Another six patents remain uncategorized, likely due to broader claims or incomplete indexing.
Tooth Regeneration: Featured Patents
Targeting USAG-1 to restart tooth development
U.S. Pat. App. No. 2025/0136674 outlines a novel therapeutic approach for treating congenital tooth agenesis, a condition for people born without certain teeth) by reactivating halted tooth development without relying on surgical transplantation. The invention centers on an antibody that neutralizes USAG-1. By blocking USAG-1, the treatment promotes the differentiation of underdeveloped tooth structures into fully formed teeth.
The patent application also describes how this antibody was shown to regenerate missing teeth and even induce extra tooth formation in mouse models. The antibody is designed for high specificity, targeting USAG-1 through complementarity-determining regions (CDRs) with at least 90% sequence identity to reference sequences.
Claims cover multiple variants, including those with modified heavy and light chains, humanized or chimeric forms, and competitive binding analogs. These antibodies may be formulated into pharmaceutical compositions for use in dental regenerative therapies, offering a non-invasive option to stimulate natural tooth regrowth.
The patent application, titled “Usag-1 molecule-targeting neutralizing antibody for tooth regeneration treatment”, was filed on February 3, 2022, and was published on May 1, 2025. The application lists Katsu Takahashi, Manabu Sugai,Yoshihito Tokita, Junichi Takagi, and Emiko Mihara as inventors. Legal representation was provided by Morgan, Lewis & Bockius LLP.
Implant design for erupting or regenerating teeth
JP2023028834A describes a specialized dental implant designed to accommodate newly erupting or regenerating teeth within the alveolar bone. The implant features an abutment, a connector that links the implant body to a prosthetic tooth or structure, providing support during the treatment period.
The implant body consists of two distinct material regions:
- A non-bioabsorbable upper section that ensures long-term structural stability
- A bioabsorbable lower section that gradually resorbs as the natural tooth continues to emerge
By combining materials with different resorption rates, the implant offers stable yet temporary support, enabling continued natural eruption. This design presents a practical solution for managing teeth during developmental stages or regenerative therapies.
The patent application, titled “Implant body and dental implant”, was filed on August 20, 2021, and was published on March 3, 2023. Mitsuru Kimura, Seita Yamanaka, Shiro Tatsutake, and Tomoko Wada from Ashida & Kimura represented Toregem Biopharma in the patent filing. The inventor listed is Honoka Kiso.
Honoka Kiso’s work is closely linked to that of Dr. Katsu Takahashi, whose research on USAG-1 at Kyoto University helped lay the groundwork for tooth regeneration therapy. Kiso was part of Dr. Takahashi’s research team and helped turn his discoveries into a commercial product. Now the CEO and co-founder of Toregem Biopharma, she is leading efforts to bring this science from the lab to real-world dental treatments. Their work shows how academic research can grow into a startup focused on clinical solutions.
The Future of Tooth Regeneration
TRG-035 has gained worldwide attention as the first drug candidate specifically developed to regenerate teeth. Its approach, which blocks the USAG-1 protein to reactivate dormant tooth buds, is currently the most advanced in clinical development.
Other research groups are investigating complementary strategies. At King’s College London, Professor Paul Sharpe and his team are exploring stem cell-based methods to generate new teeth by studying the molecular signals that guide tooth formation. Meanwhile, researchers at the University of Hong Kong are working on enhancing pulp regeneration by preconditioning dental stem cells to improve their survival and function.
In contrast to TRG-035, which activates a biological switch to stimulate the growth of an entire tooth, many of these approaches focus on rebuilding specific dental tissues such as enamel, dentin, or pulp, using stem cells and engineered materials. Together, they represent two directions toward the same goal. One aims to restart complete tooth development, while the other focuses on repairing or regenerating individual components.
Although TRG-035 is the first to enter human trials, the wider field of regenerative dentistry is advancing on multiple fronts, each offering potential solutions to tooth loss and damage.
