Development of preventive therapy for Alzheimer's disease by modification in expressional levels of the risk genes

2022 Fiscal Year Final Research Report

• Project/Area Number: 19H03546
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Nishimura Masaki 滋賀医科大学, 神経難病研究センター, 教授 (40322739)
• Co-Investigator(Kenkyū-buntansha): 中野 将希 滋賀医科大学, 神経難病研究センター, 助教 (00823890) ; 渡邊 直希 滋賀医科大学, 神経難病研究センター, 助教 (60769339)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: アルツハイマー病 / リスク遺伝子 / ゲノム編集 / アミロイドβ / FAM3C / APP

Outline of Final Research Achievements

Prevention or reduction of brain amyloid-beta deposition in the preclinical stage is recognized as essential for the development of disease-modifying therapies for Alzheimer’s disease (AD). According to our previous studies, diminished expression of FAM3C in brain might be a potential risk for amyloid-beta accumulation, whereas interventions to induce FAM3C expression may be beneficial to early AD. CRISPR-deactivated Cas9 has recently emerged as a useful system for genome editing as well as epigenome and transcriptome perturbation. Due to several advantages, it has been widely adopted for a variety of applications. In this project, we have generated CRISPR-dCas9 systems for non-editing transcriptional regulation of AD risk genes, APP and FAM3C. We confirmed successful decrease and increase in APP and FMA3C expression levels in model mouse brains, respectively. This study provides proof-of-concept for clinical application of these CRISPR-dCas9 systems.

Free Research Field

脳病態学

Academic Significance and Societal Importance of the Research Achievements

従来の遺伝子治療に比しての優位性は、ゲノム改変を伴わない、オフターゲットが少ない、核酸の不安定性や免疫原性による問題がない、誘導と抑制の両方向デザインができる等である。様々なデザインによる微調節を可能にする可変性を有するところにも創造性が見出せる。一方、Alzheimer病の臨床治験の効果は乏しく、重篤な副作用をみるなど、展望は明るいとは言えない。この状況において、本課題の成果を用い、脳Aβ蓄積のリスクを分子レベルで制御することにより、発症を予防ないし遅延する介入は大きな可能性を示唆する。脳Aβ蓄積は正常老化に伴う認知機能の低下の原因でもあることから、多くの高齢者のQOL向上にも寄与できる。