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Adenoviruses Using the Cancer Marker EphA2 as a Receptor In Vitro and In Vivo by Genetic Ligand Insertion into Different Capsid Scaffolds

Adenoviral gene therapy and oncolysis would critically benefit from targeted cell entry by genetically modified capsids. This requires both the ablation of native adenovirus tropism and the identification of ligands that remain functional in virus context. Here, we establish cell type-specific entry...

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Autores principales: Behr, Michael, Kaufmann, Johanna K., Ketzer, Patrick, Engelhardt, Sarah, Mück-Häusl, Martin, Okun, Pamela M., Petersen, Gabriele, Neipel, Frank, Hassel, Jessica C., Ehrhardt, Anja, Enk, Alexander H., Nettelbeck, Dirk M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997477/
https://www.ncbi.nlm.nih.gov/pubmed/24760010
http://dx.doi.org/10.1371/journal.pone.0095723
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author Behr, Michael
Kaufmann, Johanna K.
Ketzer, Patrick
Engelhardt, Sarah
Mück-Häusl, Martin
Okun, Pamela M.
Petersen, Gabriele
Neipel, Frank
Hassel, Jessica C.
Ehrhardt, Anja
Enk, Alexander H.
Nettelbeck, Dirk M.
author_facet Behr, Michael
Kaufmann, Johanna K.
Ketzer, Patrick
Engelhardt, Sarah
Mück-Häusl, Martin
Okun, Pamela M.
Petersen, Gabriele
Neipel, Frank
Hassel, Jessica C.
Ehrhardt, Anja
Enk, Alexander H.
Nettelbeck, Dirk M.
author_sort Behr, Michael
collection PubMed
description Adenoviral gene therapy and oncolysis would critically benefit from targeted cell entry by genetically modified capsids. This requires both the ablation of native adenovirus tropism and the identification of ligands that remain functional in virus context. Here, we establish cell type-specific entry of HAdV-5-based vectors by genetic ligand insertion into a chimeric fiber with shaft and knob domains of the short HAdV-41 fiber (Ad5T/41sSK). This fiber format was reported to ablate transduction in vitro and biodistribution to the liver in vivo. We show that the YSA peptide, binding to the pan-cancer marker EphA2, can be inserted into three positions of the chimeric fiber, resulting in strong transduction of EphA2-positive but not EphA2-negative cells of human melanoma biopsies and of tumor xenografts after intratumoral injection. Transduction was blocked by soluble YSA peptide and restored for EphA2-negative cells after recombinant EphA2 expression. The YSA peptide could also be inserted into three positions of a CAR binding-ablated HAdV-5 fiber enabling specific transduction; however, the Ad5T/41sSK format was superior in vivo. In conclusion, we establish an adenovirus capsid facilitating functional insertion of targeting peptides and a novel adenovirus using the tumor marker EphA2 as receptor with high potential for cancer gene therapy and viral oncolysis.
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spelling pubmed-39974772014-04-29 Adenoviruses Using the Cancer Marker EphA2 as a Receptor In Vitro and In Vivo by Genetic Ligand Insertion into Different Capsid Scaffolds Behr, Michael Kaufmann, Johanna K. Ketzer, Patrick Engelhardt, Sarah Mück-Häusl, Martin Okun, Pamela M. Petersen, Gabriele Neipel, Frank Hassel, Jessica C. Ehrhardt, Anja Enk, Alexander H. Nettelbeck, Dirk M. PLoS One Research Article Adenoviral gene therapy and oncolysis would critically benefit from targeted cell entry by genetically modified capsids. This requires both the ablation of native adenovirus tropism and the identification of ligands that remain functional in virus context. Here, we establish cell type-specific entry of HAdV-5-based vectors by genetic ligand insertion into a chimeric fiber with shaft and knob domains of the short HAdV-41 fiber (Ad5T/41sSK). This fiber format was reported to ablate transduction in vitro and biodistribution to the liver in vivo. We show that the YSA peptide, binding to the pan-cancer marker EphA2, can be inserted into three positions of the chimeric fiber, resulting in strong transduction of EphA2-positive but not EphA2-negative cells of human melanoma biopsies and of tumor xenografts after intratumoral injection. Transduction was blocked by soluble YSA peptide and restored for EphA2-negative cells after recombinant EphA2 expression. The YSA peptide could also be inserted into three positions of a CAR binding-ablated HAdV-5 fiber enabling specific transduction; however, the Ad5T/41sSK format was superior in vivo. In conclusion, we establish an adenovirus capsid facilitating functional insertion of targeting peptides and a novel adenovirus using the tumor marker EphA2 as receptor with high potential for cancer gene therapy and viral oncolysis. Public Library of Science 2014-04-23 /pmc/articles/PMC3997477/ /pubmed/24760010 http://dx.doi.org/10.1371/journal.pone.0095723 Text en © 2014 Behr et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Behr, Michael
Kaufmann, Johanna K.
Ketzer, Patrick
Engelhardt, Sarah
Mück-Häusl, Martin
Okun, Pamela M.
Petersen, Gabriele
Neipel, Frank
Hassel, Jessica C.
Ehrhardt, Anja
Enk, Alexander H.
Nettelbeck, Dirk M.
Adenoviruses Using the Cancer Marker EphA2 as a Receptor In Vitro and In Vivo by Genetic Ligand Insertion into Different Capsid Scaffolds
title Adenoviruses Using the Cancer Marker EphA2 as a Receptor In Vitro and In Vivo by Genetic Ligand Insertion into Different Capsid Scaffolds
title_full Adenoviruses Using the Cancer Marker EphA2 as a Receptor In Vitro and In Vivo by Genetic Ligand Insertion into Different Capsid Scaffolds
title_fullStr Adenoviruses Using the Cancer Marker EphA2 as a Receptor In Vitro and In Vivo by Genetic Ligand Insertion into Different Capsid Scaffolds
title_full_unstemmed Adenoviruses Using the Cancer Marker EphA2 as a Receptor In Vitro and In Vivo by Genetic Ligand Insertion into Different Capsid Scaffolds
title_short Adenoviruses Using the Cancer Marker EphA2 as a Receptor In Vitro and In Vivo by Genetic Ligand Insertion into Different Capsid Scaffolds
title_sort adenoviruses using the cancer marker epha2 as a receptor in vitro and in vivo by genetic ligand insertion into different capsid scaffolds
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997477/
https://www.ncbi.nlm.nih.gov/pubmed/24760010
http://dx.doi.org/10.1371/journal.pone.0095723
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