Cargando…
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...
Autores principales: | , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782313195817402368 |
---|---|
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. |
format | Online Article Text |
id | pubmed-3997477 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT behrmichael adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds AT kaufmannjohannak adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds AT ketzerpatrick adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds AT engelhardtsarah adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds AT muckhauslmartin adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds AT okunpamelam adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds AT petersengabriele adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds AT neipelfrank adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds AT hasseljessicac adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds AT ehrhardtanja adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds AT enkalexanderh adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds AT nettelbeckdirkm adenovirusesusingthecancermarkerepha2asareceptorinvitroandinvivobygeneticligandinsertionintodifferentcapsidscaffolds |