1: Development of a Method to Restore the Function of Lost Genes in Prader-Willi Syndrome Using Epigenome Editing Technology
Science of the Month - December 2025
1: Development of a Method to Restore the Function of Lost Genes in Prader-Willi Syndrome Using Epigenome Editing Technology
Nature Communications.
Akisa Nemoto, Kent Imaizumi, Fuyuki Miya, Yuka Hiroi, Mamiko Yamada, Hirosato Ideno, Shinji Saitoh, Kenjiro Kosaki, Hironobu Okuno, Hideyuki Okano
Prader-Willi Syndrome (PWS) is a congenital disorder caused by the loss of gene function in a specific region of the paternal chromosome 15, presenting with diverse symptoms such as hypotonia, developmental delay, hyperphagia/obesity, and hormonal abnormalities. The cause is attributed to hypothalamic dysfunction, and no fundamental treatment exists. Patients possess the same genes on the maternal chromosome, but their expression is suppressed by epigenomic modifications. Reversing this silencing to reactivate maternal genes could lead to improved pathology. In this study, the CRISPR/dCas9-SunTag-TET1 system was applied to iPS cells derived from PWS patients to remove DNA methylation and reactivate maternal genes. As a result, gene expression was maintained even after differentiation into hypothalamic organoids, and single-cell analysis confirmed the recovery of abnormal expression patterns with no off-target effects observed, showing promise in terms of safety. This marks the first time in the world that PWS-related genes have been shown to be restorable via epigenome editing in a human cell model. Future expectations include validation in animal models and clinical applications, application to other imprinting disorders such as Angelman syndrome, and the establishment of safe and sustainable gene therapy methods. (Comprehensive methylation analysis was conducted as a joint research project with Professor Kosaki (68th Class) of the Center for Medical Genetics.)
(Hideyuki Okano, Professor and Director, Keio University Regenerative Medicine Research Center (KRM) / Hironobu Okuno, Associate Professor, Department of Pediatrics and Adolescent Medicine, Tokyo Medical University)
2: Antigen-Specific Treatment by Converting "Disease-Causing Cells" into "Suppressive Cells"
Science Translational Medicine.
Miho Mukai, Hayato Takahashi, Yoko Kubo, Yasuhiko Asahina, Hisato Iriki, Hisashi Nomura, Aki Kamata, Hiromi Ito, Yutaka Kurebayashi, Jun Yamagami, Norihisa Mikami, Shimon Sakaguchi, Masayuki Amagai
Pemphigus vulgaris (PV) is an autoimmune disease that causes systemic blistering due to autoantibodies against desmoglein 3 (Dsg3). Induced regulatory T cells (iTreg) are a promising therapeutic tool combining antigen specificity with high proliferative capacity, but their unstable immune-suppressive ability has been a barrier to clinical application. In this study, conducted in collaboration with Osaka University (Professor Shimon Sakaguchi), we aimed for therapeutic application to PV using iTregs stabilized by inducing demethylation of the Foxp3 gene. When Dsg3-specific stabilized iTregs were administered to PV model mice, the total number of B cells remained unchanged, but the number of Dsg3-specific B cells was suppressed. Furthermore, anti-Dsg3 antibody titers and skin symptoms were significantly suppressed, demonstrating that PV is inhibited in an antigen-specific manner. Additionally, aiming for future clinical application, we optimized the induction conditions for stabilized iTregs from peripheral blood T cells of PV patients, confirming Foxp3 gene demethylation and inhibitory effects in vitro. This treatment method involves converting pathogenic T cells into stabilized iTregs that suppress the disease without genetic modification and returning them to the patient. It is expected to become a more effective treatment with fewer side effects for autoimmune diseases that have been considered difficult to treat.
(Miho Mukai, Department of Dermatology)