Mechanisms of treatment of Rett syndrome with ghrelin administration

• Project/Area Number: 18K15692
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kurume University
• Principal Investigator: Yuge Kotaro 久留米大学, 医学部, 助教 (20624472)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: レット症候群 / グレリン / 治療メカニズム / 神経伝達物質 / 睡眠障害 / 自律神経 / 睡眠 / モノアミン系神経回路 / マイクロダイアリシス / モデルマウス / 遺伝子発現 / 治療 / レット症候群モデルマウス

Outline of Final Research Achievements

Rett syndrome (RTT) is a neurodevelopmental disorder that develops in infancy and is characterised by severe intellectual disability, autism, epilepsy, sleep disturbance and dystonia, and is mainly caused by MeCP2 mutations. The applicant has focused on the diverse physiological activities of ghrelin, a gastric and intestinal hormone, and has conducted research on RTT treatment with ghrelin. As a result of this research, the therapeutic mechanism was analysed using an RTT model (MeCP2-deficient) mouse, as it was found that the treatment improved dystonia, sleep and constipation. The study found that improvement of dopamine and noradrenaline reactivity as well as improvement of the autonomic nervous system were suggested as treatment mechanisms.

Academic Significance and Societal Importance of the Research Achievements

本研究では、グレリン治療のメカニズムとしてRTTモデルマウスにてドパミン・ノルアドレナリン反応性の改善、また自律神経症状の改善が示唆されることを見出した。これらの成果は臨床におけるRTTに対するグレリン治療法開発の一助となる可能性がある。また本研究の評価方法や結果はRTTの病態解明へつながり、さらに自閉症や知的障害などの神経発達症、また付随することの多い睡眠障害やてんかんなどの病態解明にもつながる可能性がある。

Research Products

• [Journal Article] Meaningful word acquisition is associated with walking ability over 10 years in Rett syndrome (2020)
  • Author(s): Saikusa T, Kawaguchi M, Tanioka T, Nabatame S, Takahashi S, Yuge K, Nagamitsu S, Takahashi T, Yamashita Y, Kobayashi Y, Hirayama C, Kakuma T, Matsuishi T, Itoh M.
  • Journal Title: Brain Dev Volume: 42(10) Issue: 10 Pages: 705-712
  • DOI: 10.1016/j.braindev.2020.06.012
  • Peer Reviewed / Open Access
• [Journal Article] Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing (2019)
  • Author(s): Iwama Kazuhiro、Mizuguchi Takeshi、Miyatake Satoko、Matsumoto Naomichi、et al
  • Journal Title: Journal of Medical Genetics Volume: - Issue: 6 Pages: 396-407
  • DOI: 10.1136/jmedgenet-2018-105775
  • Peer Reviewed / Open Access
• [Presentation] グレリンを用いたレット症候群の新規治療法開発、世界の治療開発のレビューを含めて (2021)
  • Author(s): 弓削康太郎
  • Organizer: 第63回小児神経学会学術集会
• [Presentation] MeCP2欠損マウスによるレット症候群の睡眠障害に関する研究 (2021)
  • Author(s): 弓削康太郎, 高橋知之, 松石豊次郎, 山下裕史朗
  • Organizer: 第63回小児神経学会学術集会
• [Presentation] A novel USP8 mutation cuses Rett syndrome-like phenotypes in a Japanese boy (2019)
  • Author(s): Kotaro Yuge, Yukako Yae, Aiko Isooka, Ryuta Ishii, Shinichiro Nagamitsu, Kazuhiro Iwama, Naomichi Matsumoto, Toyojiro Matsuishi, Yushiro Yamashita
  • Organizer: 15th Asian and Oceanian Congress of Child Neurology
  • Int'l Joint Research
• [Presentation] Questionnaire survey on fractures in patients with Rett syndrome (2019)
  • Author(s): Aiko Isooka, Kotaro Yuge, Yukako Yae, Tomoyuki Takahashi, Toyojiro Matsuishi, Yushiro Yamashita
  • Organizer: 15th Asian and Oceanian Congress of Child Neurology
  • Int'l Joint Research