2022 Fiscal Year Final Research Report
International research project on nucleic acid aptamers and their exosome-based application to therapeutics for synucleinopathy
| Project/Area Number |
20KK0126
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| Research Category |
Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 37:Biomolecular chemistry and related fields
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
泉尾 直孝 富山大学, 学術研究部薬学・和漢系, 助教 (50722261)
水口 賢司 大阪大学, 蛋白質研究所, 教授 (50450896)
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| Project Period (FY) |
2020-10-27 – 2023-03-31
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| Keywords | アプタマー / エクソソーム / 神経変性疾患 / 計算科学 / 核酸医薬 / ドラッグデリバリーシステム / αシヌクレイン / 国際共同研究 |
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| Outline of Final Research Achievements |
RNA aptamers are characterized with high affinity and selectivity to target molecules. This study aimed to develop an RNA aptamer for the N-terminal region of α-synuclein (αSyn), a presynaptic neuronal protein that is linked genetically and neuropathologically to Parkinson's disease (PD), and to establish its therapeutic basis. Using in vitro SELEX and in silico analysis, anti-N-terminal RNA aptamer (1R6) was obtained. 1R6 strongly inhibited in vitro aggregation and intercellular transmission of αSyn. The binding of 1R6 to intracellular accumulations of αSyn in a mouse model of Parkinson’s disease indicates that 1R6 could be a promising drug lead for the treatment of synucleinopathies. Moreover, we developed a technological basis using artificial exosomes with the enhanced permeability to the blood-brain barrier, so the efficient brain delivery toward therapeutics is expected.
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| Free Research Field |
ケミカルバイオロジー
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| Academic Significance and Societal Importance of the Research Achievements |
αSyn凝集体の蓄積はパーキンソン病の病理的特徴の一つであることから，その検出薬は研究を進める上で重要である．しかし従来の検出薬は分解や切断を受けやすいαSynのC末領域に対するものが大半であり，凝集に重要なN末領域は正電荷をもつ繰返し配列が集中することから，抗体には認識されにくいという長年の課題があった．そこで負電荷が多いRNAアプタマーは，本課題の打開策になりうると考えた末，1R6の開発に成功した．1R6は従来抗体では認識できなかったαSyn凝集体を捉えている可能性があり，学術的意義は高い．脳内送達を可能にする人工エクソソーム技術と組み合わせることで治療応用が期待され，社会的にも意義深い．
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