Design of siRNA-based prodrug-type therapeutics for familial hypercholesterolemia

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K05702
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37010:Bio-related chemistry
• Research Institution: Osaka Medical and Pharmaceutical University (2021); Osaka University of Pharmaceutical Sciences (2019-2020)
• Principal Investigator: Urata Hidehito 大阪医科薬科大学, 薬学部, 教授 (80211085)
• Co-Investigator(Kenkyū-buntansha): 斯波 真理子 国立研究開発法人国立循環器病研究センター, 研究所, 非常勤研究員 (70271575)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 核酸医薬 / siRNA / プロドラッグ型 / 還元環境 / 家族性高コレステロール血症

Outline of Final Research Achievements

ApoB-siRNA for familial hypercholesterolemia was designed using the originally developed prodrug-type RNA (REDUCT RNA) activated in a reducing environment. To design modification sites with REDUCT RNA, identification of degradation hotspots of ApoB-siRNA in the serum and mapping of sites that reduce the activity of ApoB-siRNA by non-prodrug type 2'-OMe modification were performed. REDUCT ApoB-siRNA designed based on these results showed that REDUCT modifications functioned effectively as a prodrug and showed a distinct superiority over 2'-OMe modifications in vitro experiments.

Free Research Field

核酸化学

Academic Significance and Societal Importance of the Research Achievements

ApoB-siRNAの血清中で分解hotspotの同定の方法論を確立できたことは、今後のsiRNAの化学修飾を行う際の指針となるものと考えている。また、既存の非プロドラッグ型2'-OMe修飾によるApoB-siRNAの活性低下部位のマッピングの結果と組み合わせることで、化学修飾を要する部位のうち、従来の非プロドラッグ型修飾が許容される部位とプロドラッグ型修飾が不可欠な部位の区別ができ、またその有用性を実験的に示すことができたことは、siRNAの化学修飾にプロドラッグ型修飾が果たせる役割を示せた結果であり、今後の実用化に向けての発展が期待できる。