Chronic cerebral palsy improved by primary tooth stem cell administration: Clinical trial underway at Nagoya University

Even for chronic cerebral palsy, for which there is no effective or radical treatment, a research group from Nagoya University and other institutions has demonstrated through experiments using rat models that improvement can be seen by using stem cells from primary teeth (baby teeth). The research has now transitioned to a clinical trial at the Nagoya University Hospital. Because primary teeth naturally fall out when replaced with permanent teeth, the physical burden on the body is minimal. There is also the advantage that a large volume of stem cells can be cultured from a single tooth. Furthermore, since the stem cells themselves possess immunomodulatory capabilities, immune rejection is unlikely to occur. As immunosuppressive drugs do not need to be used, contribution to medical economics is expected.

The research group led by Director Yoshiaki Sato, who focuses on Pediatrics and Neonatology at the Center for Maternal-Neonatal Care at Nagoya University Hospital, has been conducting research into treatments for cerebral palsy caused by hypoxic-ischemic encephalopathy around the time of birth. When cerebral palsy develops, various symptoms arise, such as walking impairments and difficulties with chewing and swallowing during meals. It is estimated that approximately 1 in 500 people in Japan develops this condition.

Cerebral palsy has various causes, including those arising when oxygen and blood flow fail to reach the brain around the time of birth, as well as those caused by genetic disorders. If a baby is found to have moderate-to-severe encephalopathy immediately after birth and is highly likely to develop cerebral palsy in the future, therapeutic hypothermia, which is a method that cools the entire body to suppress severity, is performed as the standard treatment.

However, data shows that one-quarter of the patients who receive this treatment are left with disabilities, indicating its limited effectiveness. Furthermore, the treatment has no effect unless initiated within 6 hours of birth, making therapeutic hypothermia non-applicable during the chronic phase after several months have passed.

Furthermore, while cerebral palsy is sometimes identified immediately after birth, it is usually diagnosed around 6 months to 1 year of age when medical professionals or guardians notice something unusual in motor functions. In such cases, there is no prospect of a cure through therapeutic hypothermia, and treatments primarily focus on improving supportive physical functions through rehabilitation, with limited options aiming for the recovery of the neurological function itself.

Sato and his team focused on the fact that stem cells from primary teeth have functions that protect nerves and suppress inflammation. They began research to see if it would be effective against cerebral palsy. They created cerebral palsy model rats and administered stem cells from human exfoliated deciduous teeth (SHED) during the chronic phase after neurological symptoms were fully established.

It is said that cerebral palsy model rats are less likely to display paralysis compared to humans. Therefore, to observe the effects of SHED administration more clearly, rat-specific tests were performed, such as checking motor abilities by having them cross a "ladder" suspended in the air with unevenly spaced rungs, and testing learning abilities by seeing if they could escape from a room with electrical stimulation.

Rats that received intravenous administrations of SHED three times at 5, 7, and 9 weeks of age showed improvements in motor, memory, and learning functions. It was also found that SHED was detected in the cerebrum within 24 to 48 hours after administration and was involved in activities such as newly generating nerves.

SHED is easy to collect, and its manufacturing process has been established. Generally, primary teeth naturally fall out around the age of 6 to be replaced by permanent teeth. Since a large volume of stem cells can be created from a single tooth, it can be administered not only to the individual but also distributed to others as a donor. If SHED is approved as a cellular product, SHED from other people's dental pulp can be applied, meaning it could be administered to children even before the age when their primary teeth fall out.

Moreover, any healthy tooth that is not affected by cavities can be used, from front teeth to molars. Stem cells possess immunomodulatory effects, so even though this is a SHED "transplantation," there is no need for immunosuppression or entry into a sterile room. From a medical economics standpoint, it has the potential to become an inexpensive treatment method, which is likely to lighten the burden on guardians.

At Nagoya University Hospital, a clinical trial is underway administering SHED derived from their own dental pulp to children aged 6 to 11 with cerebral palsy. Sato stated, "At present, the target age starts from 6 years old, but secondary disorders can occur in cerebral palsy after adolescence, causing various functions to decline. Since neurogenesis is thought to be more effective in younger people, it would be ideal to start treatment at an early stage and spread it as a standard treatment."

This research was supported by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research, the Ministry of Education, Culture, Sports, Science and Technology (MEXT) Moonshot Research and Development Program, the Sumitomo Electric Group CSR Foundation, the Cabinet's Programs for Bridging the gap between R&d and the IDeal society (society 5.0) and Generating Economic and social value (BRiDGE), the National Institutes for Quantum Science and Technology (QST), and Kidswell Bio (Chuo City, Tokyo Prefecture). The results were published in the electronic edition of the British scientific journal Stem Cell Research & Therapy on January 23.