Species-specific gene expression manipulation in humanized livers of chimeric mice via siRNA-encapsulated lipid nanoparticle treatment
Liver-humanized chimeric mice (PXB-mice) are widely utilized for predicting human pharmacokinetics (PK) and as human disease models. However, residual metabolic activity of mouse hepatocytes in chimeric mice can interfere with accurate human PK estimation. Lipid nanoparticle (LNP)-formulated small i...
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Elsevier
2025-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050125000610 |
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| author | Kazuto Yamazaki Kenji Kubara Go Sugahara Hiroki Muto Masae Yamamoto Yuji Mano Kaoru Mitsuhashi Chihiro Yamasaki Yuji Ishida Chise Tateno Yuta Suzuki |
| author_facet | Kazuto Yamazaki Kenji Kubara Go Sugahara Hiroki Muto Masae Yamamoto Yuji Mano Kaoru Mitsuhashi Chihiro Yamasaki Yuji Ishida Chise Tateno Yuta Suzuki |
| author_sort | Kazuto Yamazaki |
| collection | DOAJ |
| description | Liver-humanized chimeric mice (PXB-mice) are widely utilized for predicting human pharmacokinetics (PK) and as human disease models. However, residual metabolic activity of mouse hepatocytes in chimeric mice can interfere with accurate human PK estimation. Lipid nanoparticle (LNP)-formulated small interfering RNA (siRNA) treatment makes it possible to eliminate the shortcomings of chimeras and create new models. Therefore, we aimed to create a new model in which siRNA for mouse cytochrome P450 oxidoreductase (Por) gene was encapsulated in LNP and administered to PXB-mice. We validated the siRNA-LNP system in PXB-mice, showing that a single intravenous injection of LNP-formulated mouse-specific siRNA against transthyretin (Ttr) knocked down Ttr expression in the liver and decreased plasma mouse TTR levels without affecting hepatic TTR expression and plasma human TTR levels. We produced mouse Por-specific siRNA with high in vitro silencing activity (siPOR(Mm)) and confirmed the efficient knockdown of Por expression in the livers of PXB-mice administered intravenously with LNP-encapsulated siPOR (siPOR(Mm)/LNP). siPOR(Mm)/LNP treatment suppressed 4′-hydroxywarfarin, making the S-warfarin PK profile in PXB-mice more similar to that in humans. Thus, mouse-specific siRNA-LNP is a simple system to control gene expression in the remaining mouse hepatocytes of PXB-mice and create more humanized and invaluable models based on PXB-mice. |
| format | Article |
| id | doaj-art-65306dca2504448884ceea0aff34a233 |
| institution | OA Journals |
| issn | 2329-0501 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-65306dca2504448884ceea0aff34a2332025-08-20T02:29:24ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012025-06-0133210146610.1016/j.omtm.2025.101466Species-specific gene expression manipulation in humanized livers of chimeric mice via siRNA-encapsulated lipid nanoparticle treatmentKazuto Yamazaki0Kenji Kubara1Go Sugahara2Hiroki Muto3Masae Yamamoto4Yuji Mano5Kaoru Mitsuhashi6Chihiro Yamasaki7Yuji Ishida8Chise Tateno9Yuta Suzuki10Eisai Co., Ltd., Tsukuba Research Laboratories, 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, Japan; Corresponding author: Kazuto Yamazaki, Ph.D., Eisai Co., Ltd., Tsukuba Research Laboratories, 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, Japan.Eisai Co., Ltd., Tsukuba Research Laboratories, 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, JapanResearch and Development Department, PhoenixBio Co., Ltd., 3-4-1, Kagamiyama, Higashi-Hiroshima, Hiroshima 739-0046, JapanEisai Co., Ltd., Tsukuba Research Laboratories, 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, JapanEisai Co., Ltd., Tsukuba Research Laboratories, 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, JapanEisai Co., Ltd., Tsukuba Research Laboratories, 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, JapanEisai Co., Ltd., Tsukuba Research Laboratories, 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, JapanResearch and Development Department, PhoenixBio Co., Ltd., 3-4-1, Kagamiyama, Higashi-Hiroshima, Hiroshima 739-0046, JapanResearch and Development Department, PhoenixBio Co., Ltd., 3-4-1, Kagamiyama, Higashi-Hiroshima, Hiroshima 739-0046, Japan; Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, JapanResearch and Development Department, PhoenixBio Co., Ltd., 3-4-1, Kagamiyama, Higashi-Hiroshima, Hiroshima 739-0046, Japan; Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; School of Pharmaceutical Sciences, Wakayama Medical University, 25-1, Shichibancho, Wakayama 640-8156, Japan; Corresponding author: Chise Tateno, Ph.D., Research and Development Department, PhoenixBio Co., Ltd., 3-4-1, Kagamiyama, Higashi-Hiroshima, Hiroshima 739-0046, Japan.Eisai Co., Ltd., Tsukuba Research Laboratories, 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, JapanLiver-humanized chimeric mice (PXB-mice) are widely utilized for predicting human pharmacokinetics (PK) and as human disease models. However, residual metabolic activity of mouse hepatocytes in chimeric mice can interfere with accurate human PK estimation. Lipid nanoparticle (LNP)-formulated small interfering RNA (siRNA) treatment makes it possible to eliminate the shortcomings of chimeras and create new models. Therefore, we aimed to create a new model in which siRNA for mouse cytochrome P450 oxidoreductase (Por) gene was encapsulated in LNP and administered to PXB-mice. We validated the siRNA-LNP system in PXB-mice, showing that a single intravenous injection of LNP-formulated mouse-specific siRNA against transthyretin (Ttr) knocked down Ttr expression in the liver and decreased plasma mouse TTR levels without affecting hepatic TTR expression and plasma human TTR levels. We produced mouse Por-specific siRNA with high in vitro silencing activity (siPOR(Mm)) and confirmed the efficient knockdown of Por expression in the livers of PXB-mice administered intravenously with LNP-encapsulated siPOR (siPOR(Mm)/LNP). siPOR(Mm)/LNP treatment suppressed 4′-hydroxywarfarin, making the S-warfarin PK profile in PXB-mice more similar to that in humans. Thus, mouse-specific siRNA-LNP is a simple system to control gene expression in the remaining mouse hepatocytes of PXB-mice and create more humanized and invaluable models based on PXB-mice.http://www.sciencedirect.com/science/article/pii/S2329050125000610siRNAspecies specificitylipid nanoparticlechimeric micehumanized liverscytochrome P450 oxidoreductase |
| spellingShingle | Kazuto Yamazaki Kenji Kubara Go Sugahara Hiroki Muto Masae Yamamoto Yuji Mano Kaoru Mitsuhashi Chihiro Yamasaki Yuji Ishida Chise Tateno Yuta Suzuki Species-specific gene expression manipulation in humanized livers of chimeric mice via siRNA-encapsulated lipid nanoparticle treatment Molecular Therapy: Methods & Clinical Development siRNA species specificity lipid nanoparticle chimeric mice humanized livers cytochrome P450 oxidoreductase |
| title | Species-specific gene expression manipulation in humanized livers of chimeric mice via siRNA-encapsulated lipid nanoparticle treatment |
| title_full | Species-specific gene expression manipulation in humanized livers of chimeric mice via siRNA-encapsulated lipid nanoparticle treatment |
| title_fullStr | Species-specific gene expression manipulation in humanized livers of chimeric mice via siRNA-encapsulated lipid nanoparticle treatment |
| title_full_unstemmed | Species-specific gene expression manipulation in humanized livers of chimeric mice via siRNA-encapsulated lipid nanoparticle treatment |
| title_short | Species-specific gene expression manipulation in humanized livers of chimeric mice via siRNA-encapsulated lipid nanoparticle treatment |
| title_sort | species specific gene expression manipulation in humanized livers of chimeric mice via sirna encapsulated lipid nanoparticle treatment |
| topic | siRNA species specificity lipid nanoparticle chimeric mice humanized livers cytochrome P450 oxidoreductase |
| url | http://www.sciencedirect.com/science/article/pii/S2329050125000610 |
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