Dr. Kazuhiko Nakatani has focused on dynamic nucleic acid structures that undergo conformational changes within living systems and has advanced chemical biology research aimed at elucidating and controlling their functions through the development of small molecules that bind to such structures. His work has led to significant breakthroughs, particularly in the development of treatments for repeat expansion diseases associated with hereditary neurodegenerative disorders and in establishing the foundation for RNA-targeted small-molecule drug discovery. The following highlights his major achievements:

1. Innovative Research for Huntington's Disease Treatment
Huntington's disease is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats. Dr. Nakatani focused on the slip-out structures formed by CAG repeat DNA and demonstrated that small molecule NA could bind to these repeats, inhibiting their expansion and offering a novel therapeutic strategy through repeat contraction. When Huntington's disease model cells carrying 850 CAG repeats were cultured with NA, a reduction in the repeat length was observed. Furthermore, administration of NA to the striatal cells of a Huntington's disease mouse model resulted in an average reduction of three CAG repeats over four weeks. This achievement represents the first demonstration of repeat contraction induced by small molecules in both cellular and animal models, paving the way for potential curative treatments for repeat expansion disorders.

2. Research on Myotonic Dystrophy Type 1 (DM1)
DM1 is caused by the abnormal expansion of CTG repeats in the 3'-untranslated region of the DMPK gene. Dr. Nakatani hypothesized that the toxic CUG repeat RNA, the primary cause of DM1, forms hairpin structures within a dynamic equilibrium. Identifying numerous U-U mismatches within these hairpins, he developed JM642, a molecule that binds specifically to U-U mismatches. Intraperitoneal administration of 20 mg/kg JM642 in a DM1 mouse model significantly improved splicing abnormalities by approximately 80%. This research established that the dynamic equilibrium of CUG repeat RNA could serve as a therapeutic target and paved the way for new therapeutic approaches to DM1.

3. Research on Spinocerebellar Ataxia Type 31 (SCA31)
SCA31, a neurodegenerative disorder specific to the Japanese population, is caused by the toxicity of UGGAA repeat RNA. Although the folding structures of UGGAA repeats are highly diverse, Dr. Nakatani discovered that when UGGAA repeats form hairpin structures, a guanine-rich UGGAA/UGGAA internal loop is created, to which the small molecule NCD binds strongly. Feeding NCD to a Drosophila model of SCA31 ameliorated compound eye degeneration, indicating that NCD significantly reduced the toxicity of UGGAA repeat RNA in vivo. This breakthrough revealed new possibilities for SCA31 treatment. Additionally, collaborative research elucidated the structure of the NCD-UGGAA/UGGAA internal loop complex, providing clear evidence that NCD specifically binds to one of the diverse conformations of UGGAA repeats, biasing the equilibrium to induce complex formation.

4. Establishing a Foundation for RNA-Targeted Small Molecule Drug Discovery
Dr. Nakatani has made substantial contributions to the foundation of RNA-targeted small molecule drug discovery. During the early stages of RNA-targeted drug discovery, he recognized its potential and developed a fluorescence displacement assay to identify RNA-binding small molecules. This method leverages fluorescence quenching upon RNA-small molecule binding and has been utilized for screening new RNA-binding compounds. He also conducted large-scale projects in collaboration with pharmaceutical companies to identify RNA-binding molecules using surface plasmon resonance. These efforts accelerated drug discovery research. Furthermore, Dr. Nakatani facilitated interactions between Japanese pharmaceutical companies and leading RNA-targeted drug discovery researchers in the U.S., enhancing Japan's research capabilities and advancing international RNA-targeted drug discovery efforts.

5. Development of Molecular Tools to Regulate RNA Functions
Dr. Nakatani has also developed innovative molecular tools for regulating RNA functions in vivo. In the context of mRNA translation regulation, he demonstrated that the small molecule NCT8 induces ribosomal frameshifting, showcasing the feasibility of intervening in the translation process using small molecules. Additionally, he investigated back-splicing reactions critical for circRNA production and revealed that NCD interacts with UGGAA/UGGAA sequences to increase circRNA production by up to five times compared to controls. These findings established groundbreaking approaches for developing molecular tools to dynamically regulate RNA functions.

Conclusion
Based on a foundation of research targeting dynamic nucleic acid structures, Dr. Kazuhiko Nakatani has made pioneering contributions to the development of treatments for repeat expansion disorders, the establishment of RNA-targeted drug discovery platforms, and the regulation of RNA functions in vivo. His work has opened new therapeutic strategies in an era when RNA-targeted small-molecule drug discovery was considered challenging. These achievements are highly regarded as world-leading advances in chemical biology and life sciences, and they have laid an essential foundation for the development of next-generation therapeutics and advancements in the field of RNA-targeted drug discovery.

For these reasons, Dr. Kazuhiko Nakatani's accomplishments are recognized as deserving of the Chemical Society of Japan Award.