Development of innovative nucleic acid therapy enabling any gene control in cardiac and skeletal muscle

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H01016
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Nagata Tetsuya 東京医科歯科大学, 大学院医歯学総合研究科, プロジェクト准教授 (50362976)
• Co-Investigator(Kenkyū-buntansha): 原 倫太朗 東京医科歯科大学, 大学院医歯学総合研究科, プロジェクト講師 (70709766) ; 横田 隆徳 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (90231688)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ヘテロ核酸 / 心筋 / 骨格筋 / 遺伝性筋疾患 / 脂質リガンド

Outline of Final Research Achievements

Cholesterol-conjugated heteroduplex oligonucleotide (HDO)with gapmer-type ASO have achieved a 3-7-fold increase of gene knockdown effect in cardiac and skeletal muscle by systemic administration compared to ASO alone. In addition, the gene knockdown was less than 50% for 4-6 months after a single administration, indicating an overwhelmingly long period of gene suppression. Subcutaneous administration has shown sufficient gene suppression. We also have synthesized new lipid ligands and screened them, and found that some ligands are as effective as cholesterol. HDO with splice-switching oligonucleotides (SSO) also have improved the pharmacokinetics (PK) in blood, heart, and skeletal muscle, and the skipping was also increased in accordance with the improvement of PK.

Free Research Field

核酸医薬

Academic Significance and Societal Importance of the Research Achievements

これまでアンチセンス核酸で正常の心筋・骨格筋で遺伝子抑制効果が弱かったが、今回の開発でより遺伝子効果が強く、持続時間が長いヘテロ核酸の開発に成功している。また新たに同等の効果を持つ、リガンドも獲得した。またスキッピングでも従来の核酸では心筋・横隔膜での効果が弱いことが難点であったが、それを克服したヘテロ核酸を創生した。