Cargando…

Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression

Oncolytic viruses (OVs) promote the anti-tumor immune response as their replication, and the subsequent lysis of tumor cells, triggers the activation of immune-sensing pathways. Arming OVs by expressing transgenes with the potential to promote immune cell recruitment and activation is an attractive...

Descripción completa

Detalles Bibliográficos
Autores principales: Bryant, Jeffrey D., Lee, Jennifer S., De Almeida, Ana, Jacques, Judy, Chang, Ching-Hung, Fassler, William, Quéva, Christophe, Lerner, Lorena, Kennedy, Edward M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10018389/
https://www.ncbi.nlm.nih.gov/pubmed/36938543
http://dx.doi.org/10.1016/j.omto.2023.02.005
_version_ 1784907800374149120
author Bryant, Jeffrey D.
Lee, Jennifer S.
De Almeida, Ana
Jacques, Judy
Chang, Ching-Hung
Fassler, William
Quéva, Christophe
Lerner, Lorena
Kennedy, Edward M.
author_facet Bryant, Jeffrey D.
Lee, Jennifer S.
De Almeida, Ana
Jacques, Judy
Chang, Ching-Hung
Fassler, William
Quéva, Christophe
Lerner, Lorena
Kennedy, Edward M.
author_sort Bryant, Jeffrey D.
collection PubMed
description Oncolytic viruses (OVs) promote the anti-tumor immune response as their replication, and the subsequent lysis of tumor cells, triggers the activation of immune-sensing pathways. Arming OVs by expressing transgenes with the potential to promote immune cell recruitment and activation is an attractive strategy to enhance OVs’ therapeutic benefit. For picornaviruses, a family of OVs with clinical experience, the expression of a transgene is limited by multiple factors: genome physical packaging limits, high rates of recombination, and viral-mediated inhibition of transgene secretion. Here, we evaluated strategies for arming Seneca Valley virus (SVV) with relevant immunomodulatory transgenes. Specificially in the contex of arming SVV, we evaluated transgene maximum size and stabiltity, transgene secretion, and the impact of transgene inclusion on viral fitness. We find that SVV is not capable of expressing secreted payloads and has a transgene packaging capacity of ∼10% of viral genome size. To enable transgene expression, we developed SVV replicons with greater transgene size capacity and secretion capabilities. SVV replicons can be packaged in trans by virus in co-infected cells to express immunomodulatory transgenes in surrounding cells, thus providing a means to enhance the potential of this therapeutic to augment the anti-tumor immune response.
format Online
Article
Text
id pubmed-10018389
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher American Society of Gene & Cell Therapy
record_format MEDLINE/PubMed
spelling pubmed-100183892023-03-17 Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression Bryant, Jeffrey D. Lee, Jennifer S. De Almeida, Ana Jacques, Judy Chang, Ching-Hung Fassler, William Quéva, Christophe Lerner, Lorena Kennedy, Edward M. Mol Ther Oncolytics Original Article Oncolytic viruses (OVs) promote the anti-tumor immune response as their replication, and the subsequent lysis of tumor cells, triggers the activation of immune-sensing pathways. Arming OVs by expressing transgenes with the potential to promote immune cell recruitment and activation is an attractive strategy to enhance OVs’ therapeutic benefit. For picornaviruses, a family of OVs with clinical experience, the expression of a transgene is limited by multiple factors: genome physical packaging limits, high rates of recombination, and viral-mediated inhibition of transgene secretion. Here, we evaluated strategies for arming Seneca Valley virus (SVV) with relevant immunomodulatory transgenes. Specificially in the contex of arming SVV, we evaluated transgene maximum size and stabiltity, transgene secretion, and the impact of transgene inclusion on viral fitness. We find that SVV is not capable of expressing secreted payloads and has a transgene packaging capacity of ∼10% of viral genome size. To enable transgene expression, we developed SVV replicons with greater transgene size capacity and secretion capabilities. SVV replicons can be packaged in trans by virus in co-infected cells to express immunomodulatory transgenes in surrounding cells, thus providing a means to enhance the potential of this therapeutic to augment the anti-tumor immune response. American Society of Gene & Cell Therapy 2023-02-16 /pmc/articles/PMC10018389/ /pubmed/36938543 http://dx.doi.org/10.1016/j.omto.2023.02.005 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Bryant, Jeffrey D.
Lee, Jennifer S.
De Almeida, Ana
Jacques, Judy
Chang, Ching-Hung
Fassler, William
Quéva, Christophe
Lerner, Lorena
Kennedy, Edward M.
Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression
title Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression
title_full Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression
title_fullStr Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression
title_full_unstemmed Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression
title_short Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression
title_sort seneca valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10018389/
https://www.ncbi.nlm.nih.gov/pubmed/36938543
http://dx.doi.org/10.1016/j.omto.2023.02.005
work_keys_str_mv AT bryantjeffreyd senecavalleyvirusrepliconsarepackagedintransandhavethecapacitytoovercomethelimitationsofviraltransgeneexpression
AT leejennifers senecavalleyvirusrepliconsarepackagedintransandhavethecapacitytoovercomethelimitationsofviraltransgeneexpression
AT dealmeidaana senecavalleyvirusrepliconsarepackagedintransandhavethecapacitytoovercomethelimitationsofviraltransgeneexpression
AT jacquesjudy senecavalleyvirusrepliconsarepackagedintransandhavethecapacitytoovercomethelimitationsofviraltransgeneexpression
AT changchinghung senecavalleyvirusrepliconsarepackagedintransandhavethecapacitytoovercomethelimitationsofviraltransgeneexpression
AT fasslerwilliam senecavalleyvirusrepliconsarepackagedintransandhavethecapacitytoovercomethelimitationsofviraltransgeneexpression
AT quevachristophe senecavalleyvirusrepliconsarepackagedintransandhavethecapacitytoovercomethelimitationsofviraltransgeneexpression
AT lernerlorena senecavalleyvirusrepliconsarepackagedintransandhavethecapacitytoovercomethelimitationsofviraltransgeneexpression
AT kennedyedwardm senecavalleyvirusrepliconsarepackagedintransandhavethecapacitytoovercomethelimitationsofviraltransgeneexpression