Development of novel therapeutics for intractable neuropathic pain based on target protector RNA modulating HCN channel function

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K09232
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55050:Anesthesiology-related
• Research Institution: Nippon Medical School
• Principal Investigator: SUZUKI Hidenori 日本医科大学, 大学院医学研究科, 研究生 (30221328)
• Co-Investigator(Kenkyū-buntansha): 齋藤 文仁 日本医科大学, 医学部, 准教授 (20360175) ; 坂井 敦 日本医科大学, 医学部, 講師 (30386156) ; 丸山 基世 日本医科大学, 医学部, 助教 (60709757)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: HCNチャネル / microRNA / target protector / 一次感覚神経 / 神経障害性疼痛

Outline of Final Research Achievements

HCN channels are promising therapeutic targets for refractory neuropathic pain, although there are concerns about adverse effects on the heart, which expresses several types of HCN channels. In this study, we attempted to suppress HCN channel function in primary sensory neurons by modulating the expression of HCN channel regulatory subunits using antisense nucleic acids (target protectors) that can only inhibit the binding between the HCN regulatory subunit mRNAs and microRNAs that target them. Target protector candidates with high inhibitory effects were identified by screening of nucleic acid sequences around the interaction site between mRNA and microRNAs that were upregulated in primary sensory neurons after nerve injury. The results suggest the potential for development of novel therapeutics for intractable neuropathic pain based on target protector RNA modulating HCN channel function.

Free Research Field

神経薬理学

Academic Significance and Societal Importance of the Research Achievements

神経障害を伴う慢性疼痛治療に対し、数多くのイオンチャネルに対する選択的阻害薬が合成されてきたが、実臨床における有効性や安全性に課題があり、承認に至っていない。本研究の成果は、従来のようなイオンチャネル選択的阻害薬ではなく、チャネル機能を制御するサブユニットを標的にしたmicroRNAの結合を阻害するtarget protectorを治療薬とする全く新しい観点からの研究であり、HCNチャネルサブユニットの発現量を変化させるmicroRNA結合配列を標的としたtarget protectorを見出したことは、社会的に望まれている神経障害性疼痛治療薬開発の有用な突破口となる可能性がある。