Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids
Abstract AAV vectors show promise for gene therapy; however, kidney gene transfer remains challenging. Here we conduct a barcode-seq-based comparison of 47 AAV capsids administered through different routes in mice, followed by individual validation. We find that local delivery of AAV-KP1, but not AA...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-12-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54475-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559379343572992 |
|---|---|
| author | Taisuke Furusho Ranjan Das Hideyuki Hakui Anusha Sairavi Kei Adachi Mia S. Galbraith-Liss Pratheppa Rajagopal Masahiro Horikawa Shuhua Luo Lena Li Kentaro Yamada Nicole Andeen Gregory A. Dissen Hiroyuki Nakai |
| author_facet | Taisuke Furusho Ranjan Das Hideyuki Hakui Anusha Sairavi Kei Adachi Mia S. Galbraith-Liss Pratheppa Rajagopal Masahiro Horikawa Shuhua Luo Lena Li Kentaro Yamada Nicole Andeen Gregory A. Dissen Hiroyuki Nakai |
| author_sort | Taisuke Furusho |
| collection | DOAJ |
| description | Abstract AAV vectors show promise for gene therapy; however, kidney gene transfer remains challenging. Here we conduct a barcode-seq-based comparison of 47 AAV capsids administered through different routes in mice, followed by individual validation. We find that local delivery of AAV-KP1, but not AAV9, via the renal vein or pelvis effectively transduces proximal tubules with minimal off-target liver transduction, while systemic AAV9, but not AAV-KP1, enhances proximal tubule and podocyte transduction in chronic kidney disease. We demonstrate that these contrasting observations are partly due to differences in their pharmacokinetics. Importantly, we show that renal pelvis injection overcomes pre-existing immunity, leading to robust and exclusive proximal tubule transduction, in non-human primates (NHPs). In addition, we highlight drastic differences in renal transduction profiles between mice and NHPs. Thus, this study provides mechanistic insights and underscores importance of context-dependent selection of AAV capsids to overcome challenges in gene delivery to the kidney. |
| format | Article |
| id | doaj-art-9a7abb30409a48e58f1f895df1d09c47 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9a7abb30409a48e58f1f895df1d09c472025-01-05T12:34:52ZengNature PortfolioNature Communications2041-17232024-12-0115111710.1038/s41467-024-54475-9Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsidsTaisuke Furusho0Ranjan Das1Hideyuki Hakui2Anusha Sairavi3Kei Adachi4Mia S. Galbraith-Liss5Pratheppa Rajagopal6Masahiro Horikawa7Shuhua Luo8Lena Li9Kentaro Yamada10Nicole Andeen11Gregory A. Dissen12Hiroyuki Nakai13Department of Molecular and Medical Genetics, Oregon Health & Science University School of MedicineDepartment of Molecular and Medical Genetics, Oregon Health & Science University School of MedicineDepartment of Molecular and Medical Genetics, Oregon Health & Science University School of MedicineDepartment of Molecular and Medical Genetics, Oregon Health & Science University School of MedicineDepartment of Molecular and Medical Genetics, Oregon Health & Science University School of MedicineDepartment of Molecular and Medical Genetics, Oregon Health & Science University School of MedicineDepartment of Molecular and Medical Genetics, Oregon Health & Science University School of MedicineDotter Department of Interventional Radiology, Oregon Health & Science University School of MedicineDepartment of Molecular and Medical Genetics, Oregon Health & Science University School of MedicineDepartment of Molecular and Medical Genetics, Oregon Health & Science University School of MedicineDotter Department of Interventional Radiology, Oregon Health & Science University School of MedicineDepartment of Pathology, Oregon Health & Science University School of MedicineDivision of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science UniversityDepartment of Molecular and Medical Genetics, Oregon Health & Science University School of MedicineAbstract AAV vectors show promise for gene therapy; however, kidney gene transfer remains challenging. Here we conduct a barcode-seq-based comparison of 47 AAV capsids administered through different routes in mice, followed by individual validation. We find that local delivery of AAV-KP1, but not AAV9, via the renal vein or pelvis effectively transduces proximal tubules with minimal off-target liver transduction, while systemic AAV9, but not AAV-KP1, enhances proximal tubule and podocyte transduction in chronic kidney disease. We demonstrate that these contrasting observations are partly due to differences in their pharmacokinetics. Importantly, we show that renal pelvis injection overcomes pre-existing immunity, leading to robust and exclusive proximal tubule transduction, in non-human primates (NHPs). In addition, we highlight drastic differences in renal transduction profiles between mice and NHPs. Thus, this study provides mechanistic insights and underscores importance of context-dependent selection of AAV capsids to overcome challenges in gene delivery to the kidney.https://doi.org/10.1038/s41467-024-54475-9 |
| spellingShingle | Taisuke Furusho Ranjan Das Hideyuki Hakui Anusha Sairavi Kei Adachi Mia S. Galbraith-Liss Pratheppa Rajagopal Masahiro Horikawa Shuhua Luo Lena Li Kentaro Yamada Nicole Andeen Gregory A. Dissen Hiroyuki Nakai Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids Nature Communications |
| title | Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids |
| title_full | Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids |
| title_fullStr | Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids |
| title_full_unstemmed | Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids |
| title_short | Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids |
| title_sort | enhancing gene transfer to renal tubules and podocytes by context dependent selection of aav capsids |
| url | https://doi.org/10.1038/s41467-024-54475-9 |
| work_keys_str_mv | AT taisukefurusho enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT ranjandas enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT hideyukihakui enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT anushasairavi enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT keiadachi enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT miasgalbraithliss enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT prathepparajagopal enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT masahirohorikawa enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT shuhualuo enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT lenali enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT kentaroyamada enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT nicoleandeen enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT gregoryadissen enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids AT hiroyukinakai enhancinggenetransfertorenaltubulesandpodocytesbycontextdependentselectionofaavcapsids |