Novel ALS/FTLD Therapy by Targeting RNA

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07837
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Tokyo University of Science, Yamaguchi (2020-2021); Tohoku University (2019)
• Principal Investigator: Nakagawa Tadashi 山陽小野田市立山口東京理科大学, 薬学部, 講師 (30707013)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ALS / FTLD / モデルマウス / TDP-43凝集体 / RNase

Outline of Final Research Achievements

To investigate whether T-RNase, which reduces TDP-43 aggregation, a causative agent of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD), can reduce TDP-43 aggregation in vivo in ALS/FTLD model mice and improve the pathological phenotype, I tried to generate T-RNase-expressing mice.
To eliminate non-neuronal effects, we aimed to express T-RNase in a neuron-specific manner. We succeeded in creating a vector for producing genetically engineered mice that express T-RNase specifically in neurons (T-RNase neuro-Tg mice), but when I actually created the mice, I found that they died before they were born. Therefore, I switched to creating genetically engineered mice that express T-RNase in a tetracycline-inducible manner (inducible T-RNase neuro-Tg mice). Vectors for this purpose were created, but mice were not produced. On the other hand, I was able to discover a new reagent (NMS-873) that inhibits TDP-43 aggregate formation.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

T-RNaseは培養細胞では顕著な毒性を示さないものの、生体における神経細胞では細胞死を引き起こすほどの毒性を示すことが示唆された。そのため、基礎医学実験のためには有用なツールであると考えているが、医療への応用は難しいことがわかった。TDP-43の凝集体形成を阻害する試薬を発見できたが、これを医療応用する際にもマウス等モデル生物を用いた毒性検証が重要と考えられる。ALSとFTLDに対する有効な治療法の開発が望まれている。失敗のリスクが高い本研究のような内容の研究も積極的に行い、得られた情報を開示することがそのような治療法の開発に必要と考えている。