Development of a Heteroduplex Oligonucleotide Targeting MicroRNAs For Ischemic Stroke

2020 Fiscal Year Final Research Report

• Project/Area Number: 17H01548
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Satoru Ishibashi 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (30533369)
• Co-Investigator(Kenkyū-buntansha): 和田 健彦 東北大学, 多元物質科学研究所, 教授 (20220957)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 脳卒中 / 核酸医薬 / 脳血管内皮細胞 / マウス / 人工核酸 / 環境応答型核酸 / 水素イオン指数

Outline of Final Research Achievements

Brain endothelial cells (BECs) play a central role at the neurovascular unit (NVU) in acute phase of ischemic stroke. Because some microRNAs regulate endothelial function in the ischemic stroke, modulating microRNAs in endothelial cells could contribute to develop brand new therapeutics for ischemic stroke.
We recently developed a heteroduplex oligonucleotide (HDO), which effectively delivered and downregulated its target gene in BECs, and a peptide ribonucleic acids (PRNA), which regulated genes expression based on intracellular environmental condition (e.g. pH). In addition, we identified effective microRNAs for the treatment of ischemic stroke, when HUVECs were subjected to Oxygen-glucose deprivation (OGD). We aimed to open a new therapeutic field of microRNAs silencing at BECs for acute phase of ischemic stroke. In our studies, we have developed HDO targeting microRNA, which could effectively deliver and silence microRNA expressions in BECs.

Free Research Field

Neuroscience

Academic Significance and Societal Importance of the Research Achievements

脳梗塞は重篤な後遺症を起こし、時に死因となりうる国民病である。microRNAは脳梗塞において新しい治療標的分子として知られており、脳血管内皮細胞に存在するmicroRNAを制御することで、血管新生を促進させ、脳梗塞後の神経予後の改善が期待できる。本研究で検討されたmicroRNAを標的とした第二世代ヘテロ人工核酸は、以前の人工核酸と比較すると、脳血管内皮細胞への効率的なデリバリー効果や、遺伝子抑制効果を示すことができたため、より副作用が少なく、また、効果の高い人工核酸の基盤技術となり得ると考えている。