| Project/Area Number |
21F21105
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| Research Category |
Grant-in-Aid for JSPS Fellows
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| Allocation Type | Single-year Grants |
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| Section | 外国 |
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| Review Section |
Basic Section 90120:Biomaterials-related
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| Research Institution | Hokkaido University |
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Principal Investigator |
原島 秀吉 北海道大学, 薬学研究院, 教授 (00183567)
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| Co-Investigator(Kenkyū-buntansha) |
YOUNIS MAHMOUD 北海道大学, 薬学研究院, 外国人特別研究員
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| Project Period (FY) |
2021-04-28 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2022: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2021: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | 核酸医薬 / 遺伝子治療 / 脂質ナノ粒子 / hepatic stellate cells / liver fibrosis / Liver fibrosis / Hepatic Stellate Cells / mRNA / Lipid Nanoparticles / Microfluidic Device |
|---|
| Outline of Research at the Start |
This research focuses on the identification of the technical aspects controlling the in vivo performance of nucleic acids-loaded lipid nanoparticles and the factors affecting gene delivery to different liver cell populations. Tweaking the composition and physico-chemical properties of the nanocarriers to affect their interactions with endogenous serum transporter proteins is a novel targeting strategy to replace the conventional ligand-based targeting. The recruitment of mRNA as a therapeutic tool is a hot topic that will be attempted for the treatment of complicated liver diseases.
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| Outline of Annual Research Achievements |
First, lipid nanoparticles (LNPs) based on a library of molecularly-diverse ionizable lipids were screened in vitro for selective mRNA delivery to aHSCs cell line, LX-2. Second, the top-performing candidates were screened and optimized in vivo in mice undergoing liver fibrosis. The composition and physico-chemical properties of LNPs were tweaked to manipulate the endogenous protein corona that is formed around LNPs and subsequently enable ligand-free targeting. Third, the biosafety of the optimized LNPs was intensively evaluated upon either acute dose escalation or chronic administration. Fourth, the underlying mechanism for selective delivery of LNPs to aHSCs in vivo was explored using a systematic strategy. Fifth, the selected candidates were also investigated for siRNA delivery to aHSCs in vivo. Eventually, a therapeutic strategy was established based on the siRNA-mediated reprogramming of aHSCs into the quiescent state (qHSCs).
This project enabled identification of the optimum conditions for ligand-free targeting of aHSCs in vivo for the first time. Moreover, a successful gene therapy-based strategy for the treatment of liver fibrosis was established and evaluated with a promising clinical potential.
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| Research Progress Status |
令和4年度が最終年度であるため、記入しない。
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| Strategy for Future Research Activity |
令和4年度が最終年度であるため、記入しない。
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