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Adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy

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...

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Autores principales: Meumann, Nadja, Cabanes‐Creus, Marti, Ertelt, Moritz, Navarro, Renina Gale, Lucifora, Julie, Yuan, Qinggong, Nien‐Huber, Karin, Abdelrahman, Ahmed, Vu, Xuan‐Khang, Zhang, Liang, Franke, Ann‐Christin, Schmithals, Christian, Piiper, Albrecht, Vogt, Annabelle, Gonzalez‐Carmona, Maria, Frueh, Jochen T., Ullrich, Evelyn, Meuleman, Philip, Talbot, Steven R., Odenthal, Margarete, Ott, Michael, Seifried, Erhard, Schoeder, Clara T., Schwäble, Joachim, Lisowski, Leszek, Büning, Hildegard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936986/
https://www.ncbi.nlm.nih.gov/pubmed/35976053
http://dx.doi.org/10.1002/hep.32733
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author Meumann, Nadja
Cabanes‐Creus, Marti
Ertelt, Moritz
Navarro, Renina Gale
Lucifora, Julie
Yuan, Qinggong
Nien‐Huber, Karin
Abdelrahman, Ahmed
Vu, Xuan‐Khang
Zhang, Liang
Franke, Ann‐Christin
Schmithals, Christian
Piiper, Albrecht
Vogt, Annabelle
Gonzalez‐Carmona, Maria
Frueh, Jochen T.
Ullrich, Evelyn
Meuleman, Philip
Talbot, Steven R.
Odenthal, Margarete
Ott, Michael
Seifried, Erhard
Schoeder, Clara T.
Schwäble, Joachim
Lisowski, Leszek
Büning, Hildegard
author_facet Meumann, Nadja
Cabanes‐Creus, Marti
Ertelt, Moritz
Navarro, Renina Gale
Lucifora, Julie
Yuan, Qinggong
Nien‐Huber, Karin
Abdelrahman, Ahmed
Vu, Xuan‐Khang
Zhang, Liang
Franke, Ann‐Christin
Schmithals, Christian
Piiper, Albrecht
Vogt, Annabelle
Gonzalez‐Carmona, Maria
Frueh, Jochen T.
Ullrich, Evelyn
Meuleman, Philip
Talbot, Steven R.
Odenthal, Margarete
Ott, Michael
Seifried, Erhard
Schoeder, Clara T.
Schwäble, Joachim
Lisowski, Leszek
Büning, Hildegard
author_sort Meumann, Nadja
collection PubMed
description 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.
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spelling pubmed-99369862023-02-18 Adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy Meumann, Nadja Cabanes‐Creus, Marti Ertelt, Moritz Navarro, Renina Gale Lucifora, Julie Yuan, Qinggong Nien‐Huber, Karin Abdelrahman, Ahmed Vu, Xuan‐Khang Zhang, Liang Franke, Ann‐Christin Schmithals, Christian Piiper, Albrecht Vogt, Annabelle Gonzalez‐Carmona, Maria Frueh, Jochen T. Ullrich, Evelyn Meuleman, Philip Talbot, Steven R. Odenthal, Margarete Ott, Michael Seifried, Erhard Schoeder, Clara T. Schwäble, Joachim Lisowski, Leszek Büning, Hildegard Hepatology Original Articles: Liver Pathobiology 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. Lippincott Williams & Wilkins 2023-03 2023-02-17 /pmc/articles/PMC9936986/ /pubmed/35976053 http://dx.doi.org/10.1002/hep.32733 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of American Association for the Study of Liver Diseases. https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (https://creativecommons.org/licenses/by-nc/4.0/) (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/)
spellingShingle Original Articles: Liver Pathobiology
Meumann, Nadja
Cabanes‐Creus, Marti
Ertelt, Moritz
Navarro, Renina Gale
Lucifora, Julie
Yuan, Qinggong
Nien‐Huber, Karin
Abdelrahman, Ahmed
Vu, Xuan‐Khang
Zhang, Liang
Franke, Ann‐Christin
Schmithals, Christian
Piiper, Albrecht
Vogt, Annabelle
Gonzalez‐Carmona, Maria
Frueh, Jochen T.
Ullrich, Evelyn
Meuleman, Philip
Talbot, Steven R.
Odenthal, Margarete
Ott, Michael
Seifried, Erhard
Schoeder, Clara T.
Schwäble, Joachim
Lisowski, Leszek
Büning, Hildegard
Adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy
title Adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy
title_full Adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy
title_fullStr Adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy
title_full_unstemmed Adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy
title_short Adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy
title_sort adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy
topic Original Articles: Liver Pathobiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936986/
https://www.ncbi.nlm.nih.gov/pubmed/35976053
http://dx.doi.org/10.1002/hep.32733
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