Academic Journal
Adeno-associated virus serotype 2 capsid variants for improved liver-directed gene therapy
| العنوان: | Adeno-associated virus serotype 2 capsid variants for improved liver-directed gene therapy |
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| المؤلفون: | Meumann, N, Cabanes-Creus, M, Ertelt, M, Navarro, RG, Lucifora, J, Yuan, Q, Nien-Huber, K, Abdelrahman, A, Vu, XK, Zhang, L, Franke, AC, Schmithals, C, Piiper, A, Vogt, A, Gonzalez-Carmona, M, Frueh, JT, Ullrich, E, Meuleman, Philip, Talbot, SR, Odenthal, M, Ott, M, Seifried, E, Schoeder, CT, Schwäble, J, Lisowski, L, Büning, H |
| المصدر: | HEPATOLOGY ; ISSN: 0270-9139 ; ISSN: 1527-3350 |
| سنة النشر: | 2023 |
| المجموعة: | Ghent University Academic Bibliography |
| مصطلحات موضوعية: | Medicine and Health Sciences, Biology and Life Sciences |
| الوصف: | Background and Aims Current liver-directed gene therapies look for adeno-associated virus (AAV) vectors with improved efficacy. With this background, capsid engineering is explored. Whereas shuffled capsid library screenings have resulted in potent liver targeting variants with one first vector in human clinical trials, modifying natural serotypes by peptide insertion has so far been less successful. Here, we now report on two capsid variants, MLIV.K and MLIV.A, both derived from a high-throughput in vivo AAV peptide display selection screen in mice. Approach and Results The variants transduce primary murine and human hepatocytes at comparable efficiencies, a valuable feature in clinical development, and show significantly improved liver transduction efficacy, thereby allowing a dose reduction, and outperform parental AAV2 and AAV8 in targeting human hepatocytes in humanized mice. The natural heparan sulfate proteoglycan binding ability is markedly reduced, a feature that correlates with improved hepatocyte transduction. A further property that might contribute to the improved transduction efficacy is the lower capsid melting temperature. Peptide insertion also caused a moderate change in sensitivity to human sera containing anti-AAV2 neutralizing antibodies, revealing the impact of epitopes located at the basis of the AAV capsid protrusions. Conclusions In conclusion, MLIV.K and MLIV.A are AAV peptide display variants selected in immunocompetent mice with improved hepatocyte tropism and transduction efficiency. Because these features are maintained across species, MLIV variants provide remarkable potential for translation of therapeutic approaches from mice to men. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | https://biblio.ugent.be/publication/01GTWD9Z2QP1MNJK0ZCMFT6Z89; http://doi.org/10.1002/hep.32733; https://biblio.ugent.be/publication/01GTWD9Z2QP1MNJK0ZCMFT6Z89/file/01GTWDBEX9VA0AKWWGCD7WQ036 |
| DOI: | 10.1002/hep.32733 |
| الاتاحة: | https://biblio.ugent.be/publication/01GTWD9Z2QP1MNJK0ZCMFT6Z89 http://hdl.handle.net/1854/LU-01GTWD9Z2QP1MNJK0ZCMFT6Z89 https://doi.org/10.1002/hep.32733 https://biblio.ugent.be/publication/01GTWD9Z2QP1MNJK0ZCMFT6Z89/file/01GTWDBEX9VA0AKWWGCD7WQ036 |
| Rights: | Creative Commons Attribution-NonCommercial 4.0 International Public License (CC BY-NC 4.0) ; info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.FBC6F20B |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/hep.32733 |
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