Assessing the Therapeutic Potential of Alternative Splicing Manipulation in ALS Treatment for Intrinsically Disordered Regions

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07880
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Niigata University
• Principal Investigator: SUGAI Akihiro 新潟大学, 脳研究所, 助教 (70758903)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 筋萎縮性側索硬化症 / TDP-43 / 天然変性領域 / 選択的スプライシング / アンチセンスオリゴヌクレオチド

Outline of Final Research Achievements

This study aims to develop novel therapeutic strategies for Amyotrophic Lateral Sclerosis (ALS) by elucidating the role of alternative splicing of the intrinsically disordered region of the pathogenic protein TDP-43. Dysregulation of TDP-43 is known to contribute to the onset and progression of ALS, with the intrinsically disordered region potentially leading to protein misfolding, which in turn can cause fibrosis and aggregation. We have revealed the relationship between alternative splicing of TDP-43 and ALS-associated RNA-binding proteins, and have successfully developed antisense oligonucleotides to regulate this alternative splicing. The findings suggest promising avenues for the development of new therapeutic strategies for ALS.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

本研究は、ALSの発症と進行に関わる病原性タンパク質TDP-43の役割の理解を深める点で学術的意義があります。特に、TDP-43の天然変性領域、選択的スプライシング、そしてALS関連RNA結合タンパク質との関連性を明らかにし、これを制御するアンチセンスオリゴヌクレオチドを開発しました。これはALS治療の開発に向けた革新的進展であり、他の神経変性疾患への応用も期待できます。また、社会的意義としては、ALSという重篤な疾患への新治療法開発は、患者の生存期間延長とQOL向上に寄与することが期待されます。