2022 Fiscal Year Final Research Report
Design and synthesis of membrane-permeable oligonucleotides and their application to therapeutic antisense oligonucleotides
| Project/Area Number |
20K05748
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 37030:Chemical biology-related
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | オリゴ核酸 / 核酸医薬 / 細胞膜透過性 / 細胞内移行性 / 人工核酸 |
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| Outline of Final Research Achievements |
The purpose of this research is to develop oligonucleotides with cell-membrane permeability and to verify their applicability to therapeutic oligonucleotides. Focusing on membrane-permeable lipids, we have designed, synthesized and evaluated many fatty acid-conjugated oligonucleotides (antisense oligonucleotides). As a result, it was confirmed that conjugation of two palmitic acids significantly improves cellular uptake of antisense oligonucleotides. Furthermore, it was found that placing an endosomal cleavable linker between palmitic acid and the antisense oligonucleotide can improve both cellular uptake and activity of the antisense oligonucleotide.
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| Free Research Field |
核酸医薬
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| Academic Significance and Societal Importance of the Research Achievements |
アンチセンス核酸をはじめとする核酸医薬は、従来医薬では治療が困難な遺伝性疾患等に対する新たな治療手段として期待されており、実際に近年難病に対する核酸医薬品が続々と誕生してきているところである。一方で、核酸医薬は高極性なオリゴ核酸を本体とすることから細胞膜透過性（細胞内への移行性）が低く、投与したものの多くが薬効には繋がらない。本研究では、膜透過性が高い脂質を結合させることで、アンチセンス核酸の細胞内移行性並びに活性の向上を達成した。これらの技術は、高い薬効を示す核酸医薬の創出につながるものと期待される。
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