miRNA administration therapy for Rett syndrome model mice

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08224
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Institute for Developmental Research Aichi Developmental Disability Center
• Principal Investigator: Nakayama Atsuo 愛知県医療療育総合センター発達障害研究所, 細胞病態研究部, 部長 (50227964)
• Co-Investigator(Kenkyū-buntansha): 松木 亨 愛知県医療療育総合センター発達障害研究所, 細胞病態研究部, 主任研究員 (90332329)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: Rett syndrome / MECP2 / gene therapy / oligodendrocyte / AAV

Outline of Final Research Achievements

MECP2 gene, whose mutations are the common cause of Rett syndrome, is also harmful for normal CNS development, when its expression is excessive. Therefore we originally planed to search other target genes useful for the gene therapy against Rett syndrome. We originally focused on miR-199a, which is one of downstream effector of Mecp2. However, Mecp2 KO mice (Mecp2 -/y) could survive no longer than 5 weeks after birth, and were not available for gene therapy assessment. Therefore, we changed the original plan and tried to develop gene therapy vectors that enable KO mice to survive longer. Among AAV vectors to express Mecp2 itself under several different promoters including Mecp2 promotor itself, only AAV.PHP.eB-CNPpro-MeCP2-2A-RFP vector, which induce Mecp2 expression in oligodendrocyte, showed life-prolonging effects on KO mice by intravenous administration. This suggested that the early death of KO mice is due to loss of MECP2 in oligodendrocytes.

Free Research Field

病理学

Academic Significance and Societal Importance of the Research Achievements

多機能分子MECP2の遺伝子変化によるレット症候群では、原因遺伝子がわかっているにも関わらず遺伝子治療の臨床応用は困難となっている。これはMECP2を過不足なくさまざまな細胞腫で発現させることが必要だが、それが難しいためである。今回の研究ではレット症候群遺伝子治療に向けて、神経細胞のみでなくオリゴデンドログリアでのMECP2発現回復が生命予後改善に重要であることが示唆された。