| Project/Area Number |
18K14363
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 37030:Chemical biology-related
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
WADA FUMITO 国立研究開発法人国立循環器病研究センター, 研究所, 特任研究員 (90760843)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | アンチセンス / リガンド / DDS / 安全性 / 核酸医薬 |
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| Outline of Final Research Achievements |
One of the toxic effects of antisense oligonucleotides (ASOs) is renal injury due to excess accumulation of ASOs. We invented two novel designs of ASOs for avoiding the renal accumulation of ASOs.
It is known that molecules having high molecular weight are less filtered at the glomerulus. Thus, firstly, in order to increase the molecular size of ASOs, we developed ASOs that formulate the multimeric complex. We demonstrated the formulation of the tetrameric ASOs and verified the in vivo efficacy.
Secondly, we designed lipophilic ASOs. Lipophilic molecules bind albumin in the blood, and its half-life in blood is elongated. We conjugated cholesterol or palmitic acid to ASOs. Cholesterol conjugation strategy succeeded in reducing the renal accumulation of ASOs while maintaining the efficacy of ASOs.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究成果は、アンチセンス分子の活性を損なわず様々な分子の修飾や設計を可能にしたことから、アンチセンス分子の体内動態を制御するための学術的に重要な知見である。また、アンチセンス分子の腎臓への蓄積を大幅に抑制することに成功したことから、アンチセンス医薬の主な毒性の一つである腎障害を克服し得、アンチセンスという新たな分野の医薬開発に貢献する社会的にも意義のある成果と言える。
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