Engineered AAV capsids mediate transduction of murine neurofibroma and sciatic nerve
Genetic diseases such as Neurofibromatosis type 1 (NF1) and Charcot-Marie Tooth disease involve Schwann cells (SCs) associated with peripheral nerves. Gene therapy using adeno-associated virus (AAV) vector mediated gene delivery is a promising strategy to treat these diseases. However, AAV-mediated...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2025
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| Online Access: | http://psasir.upm.edu.my/id/eprint/120712/ http://psasir.upm.edu.my/id/eprint/120712/1/120712.pdf |
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| author | Abou Haidar, Edwina Prabhakar, Shilpa Cheah, Pike See Hanlon, Killian S. Espinoza, Paula Crain, Adam V. Patel, Nikita Radcliff, Greta W. Cheng, Ming Hernández, Iván Coto Minderler, Steven de la Cruz, Demitri Ng, Carrie da Hora, Cintia Carla Charest, Alain Stemmer-Rachamimov, Anat Jowett, Nate Breakefield, Xandra O. Maguire, Casey A. |
| author_facet | Abou Haidar, Edwina Prabhakar, Shilpa Cheah, Pike See Hanlon, Killian S. Espinoza, Paula Crain, Adam V. Patel, Nikita Radcliff, Greta W. Cheng, Ming Hernández, Iván Coto Minderler, Steven de la Cruz, Demitri Ng, Carrie da Hora, Cintia Carla Charest, Alain Stemmer-Rachamimov, Anat Jowett, Nate Breakefield, Xandra O. Maguire, Casey A. |
| author_sort | Abou Haidar, Edwina |
| building | UPM Institutional Repository |
| collection | Online Access |
| description | Genetic diseases such as Neurofibromatosis type 1 (NF1) and Charcot-Marie Tooth disease involve Schwann cells (SCs) associated with peripheral nerves. Gene therapy using adeno-associated virus (AAV) vector mediated gene delivery is a promising strategy to treat these diseases. However, AAV-mediated transduction of SCs in vivo after intravascular delivery is relatively inefficient, with a lack of extensive characterization of different capsids to date. Here, we performed an in vivo selection with an AAV9 capsid peptide display library in a mouse model of NF1. We chose one capsid variant, AAV-SC3, which was present in NF1 nerves for comparison to two benchmark capsids after systemic injection. AAV-SC3 significantly outperformed one of the two benchmark capsids at levels of transgene mRNA in the neurofibroma. Immunofluorescence microscopy revealed transgene expressing Sox10-positive SCs throughout the neurofibroma with AAV-SC3 injection. Next, we performed a pooled screen with four of the top capsids from our initial selection and AAV9 and identified one capsid, AAV-SC4, with enhanced biodistribution to and transduction of normal sciatic nerve in mice. This capsid displayed a peptide with a known laminin-binding motif, which may provide a conduit for future laminin-targeting strategies. Our results provide a baseline for future AAV-based gene therapies developed for NF1 or other diseases that affect SCs. |
| first_indexed | 2025-11-15T14:48:56Z |
| format | Article |
| id | upm-120712 |
| institution | Universiti Putra Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-15T14:48:56Z |
| publishDate | 2025 |
| publisher | Springer Nature |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | upm-1207122025-10-08T07:34:58Z http://psasir.upm.edu.my/id/eprint/120712/ Engineered AAV capsids mediate transduction of murine neurofibroma and sciatic nerve Abou Haidar, Edwina Prabhakar, Shilpa Cheah, Pike See Hanlon, Killian S. Espinoza, Paula Crain, Adam V. Patel, Nikita Radcliff, Greta W. Cheng, Ming Hernández, Iván Coto Minderler, Steven de la Cruz, Demitri Ng, Carrie da Hora, Cintia Carla Charest, Alain Stemmer-Rachamimov, Anat Jowett, Nate Breakefield, Xandra O. Maguire, Casey A. Genetic diseases such as Neurofibromatosis type 1 (NF1) and Charcot-Marie Tooth disease involve Schwann cells (SCs) associated with peripheral nerves. Gene therapy using adeno-associated virus (AAV) vector mediated gene delivery is a promising strategy to treat these diseases. However, AAV-mediated transduction of SCs in vivo after intravascular delivery is relatively inefficient, with a lack of extensive characterization of different capsids to date. Here, we performed an in vivo selection with an AAV9 capsid peptide display library in a mouse model of NF1. We chose one capsid variant, AAV-SC3, which was present in NF1 nerves for comparison to two benchmark capsids after systemic injection. AAV-SC3 significantly outperformed one of the two benchmark capsids at levels of transgene mRNA in the neurofibroma. Immunofluorescence microscopy revealed transgene expressing Sox10-positive SCs throughout the neurofibroma with AAV-SC3 injection. Next, we performed a pooled screen with four of the top capsids from our initial selection and AAV9 and identified one capsid, AAV-SC4, with enhanced biodistribution to and transduction of normal sciatic nerve in mice. This capsid displayed a peptide with a known laminin-binding motif, which may provide a conduit for future laminin-targeting strategies. Our results provide a baseline for future AAV-based gene therapies developed for NF1 or other diseases that affect SCs. Springer Nature 2025 Article PeerReviewed text en http://psasir.upm.edu.my/id/eprint/120712/1/120712.pdf Abou Haidar, Edwina and Prabhakar, Shilpa and Cheah, Pike See and Hanlon, Killian S. and Espinoza, Paula and Crain, Adam V. and Patel, Nikita and Radcliff, Greta W. and Cheng, Ming and Hernández, Iván Coto and Minderler, Steven and de la Cruz, Demitri and Ng, Carrie and da Hora, Cintia Carla and Charest, Alain and Stemmer-Rachamimov, Anat and Jowett, Nate and Breakefield, Xandra O. and Maguire, Casey A. (2025) Engineered AAV capsids mediate transduction of murine neurofibroma and sciatic nerve. Gene Therapy, 32 (4). pp. 385-397. ISSN 0969-7128; eISSN: 1476-5462 https://www.nature.com/articles/s41434-025-00542-9?error=cookies_not_supported&code=b32cb9ec-f337-4c46-868a-ee66fac16f7c 10.1038/s41434-025-00542-9 |
| spellingShingle | Abou Haidar, Edwina Prabhakar, Shilpa Cheah, Pike See Hanlon, Killian S. Espinoza, Paula Crain, Adam V. Patel, Nikita Radcliff, Greta W. Cheng, Ming Hernández, Iván Coto Minderler, Steven de la Cruz, Demitri Ng, Carrie da Hora, Cintia Carla Charest, Alain Stemmer-Rachamimov, Anat Jowett, Nate Breakefield, Xandra O. Maguire, Casey A. Engineered AAV capsids mediate transduction of murine neurofibroma and sciatic nerve |
| title | Engineered AAV capsids mediate transduction of murine neurofibroma and sciatic nerve |
| title_full | Engineered AAV capsids mediate transduction of murine neurofibroma and sciatic nerve |
| title_fullStr | Engineered AAV capsids mediate transduction of murine neurofibroma and sciatic nerve |
| title_full_unstemmed | Engineered AAV capsids mediate transduction of murine neurofibroma and sciatic nerve |
| title_short | Engineered AAV capsids mediate transduction of murine neurofibroma and sciatic nerve |
| title_sort | engineered aav capsids mediate transduction of murine neurofibroma and sciatic nerve |
| url | http://psasir.upm.edu.my/id/eprint/120712/ http://psasir.upm.edu.my/id/eprint/120712/ http://psasir.upm.edu.my/id/eprint/120712/ http://psasir.upm.edu.my/id/eprint/120712/1/120712.pdf |