Cargando…
Systemic and local immune responses to intraocular AAV vector administration in non-human primates
Positive clinical outcomes in adeno-associated virus (AAV)-mediated retinal gene therapy have often been attributed to the low immunogenicity of AAVs and immune privilege of the eye. However, several recent studies have shown potential for inflammatory responses. The current understanding of the fac...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844404/ https://www.ncbi.nlm.nih.gov/pubmed/35229004 http://dx.doi.org/10.1016/j.omtm.2022.01.011 |
_version_ | 1784651467823513600 |
---|---|
author | Ail, Divya Ren, Duohao Brazhnikova, Elena Nouvel-Jaillard, Céline Bertin, Stephane Mirashrafi, Seyed Bagher Fisson, Sylvain Dalkara, Deniz |
author_facet | Ail, Divya Ren, Duohao Brazhnikova, Elena Nouvel-Jaillard, Céline Bertin, Stephane Mirashrafi, Seyed Bagher Fisson, Sylvain Dalkara, Deniz |
author_sort | Ail, Divya |
collection | PubMed |
description | Positive clinical outcomes in adeno-associated virus (AAV)-mediated retinal gene therapy have often been attributed to the low immunogenicity of AAVs and immune privilege of the eye. However, several recent studies have shown potential for inflammatory responses. The current understanding of the factors contributing to inflammation, such as the pre-existence of serum antibodies against AAVs and their contribution to increases in antibody levels post-injection, is incomplete. The parameters that regulate the generation of new antibodies in response to the AAV capsid or transgene after intraocular injections are also insufficiently described. This study is a retrospective analysis of the pre-existing serum antibodies in correlation with changes in antibody levels after intraocular injections of AAV in non-human primates (NHPs) of the species Macaca fascicularis. In NHP serums, we analyzed the binding antibody (BAB) levels and a subset of these called neutralizing antibodies (NABs) that impede AAV transduction. We observed significantly higher pre-existing serum BABs against AAV8 compared with other serotypes and a dose-dependent increase in BABs and NABs in the serums collected post-injection, irrespective of the serotype or the mode of injection. Lastly, we were able to demonstrate a correlation between the serum BAB levels with clinical grading of inflammation and levels of transgene expression. |
format | Online Article Text |
id | pubmed-8844404 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-88444042022-02-27 Systemic and local immune responses to intraocular AAV vector administration in non-human primates Ail, Divya Ren, Duohao Brazhnikova, Elena Nouvel-Jaillard, Céline Bertin, Stephane Mirashrafi, Seyed Bagher Fisson, Sylvain Dalkara, Deniz Mol Ther Methods Clin Dev Original Article Positive clinical outcomes in adeno-associated virus (AAV)-mediated retinal gene therapy have often been attributed to the low immunogenicity of AAVs and immune privilege of the eye. However, several recent studies have shown potential for inflammatory responses. The current understanding of the factors contributing to inflammation, such as the pre-existence of serum antibodies against AAVs and their contribution to increases in antibody levels post-injection, is incomplete. The parameters that regulate the generation of new antibodies in response to the AAV capsid or transgene after intraocular injections are also insufficiently described. This study is a retrospective analysis of the pre-existing serum antibodies in correlation with changes in antibody levels after intraocular injections of AAV in non-human primates (NHPs) of the species Macaca fascicularis. In NHP serums, we analyzed the binding antibody (BAB) levels and a subset of these called neutralizing antibodies (NABs) that impede AAV transduction. We observed significantly higher pre-existing serum BABs against AAV8 compared with other serotypes and a dose-dependent increase in BABs and NABs in the serums collected post-injection, irrespective of the serotype or the mode of injection. Lastly, we were able to demonstrate a correlation between the serum BAB levels with clinical grading of inflammation and levels of transgene expression. American Society of Gene & Cell Therapy 2022-01-22 /pmc/articles/PMC8844404/ /pubmed/35229004 http://dx.doi.org/10.1016/j.omtm.2022.01.011 Text en © 2022 The Authors 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 Ail, Divya Ren, Duohao Brazhnikova, Elena Nouvel-Jaillard, Céline Bertin, Stephane Mirashrafi, Seyed Bagher Fisson, Sylvain Dalkara, Deniz Systemic and local immune responses to intraocular AAV vector administration in non-human primates |
title | Systemic and local immune responses to intraocular AAV vector administration in non-human primates |
title_full | Systemic and local immune responses to intraocular AAV vector administration in non-human primates |
title_fullStr | Systemic and local immune responses to intraocular AAV vector administration in non-human primates |
title_full_unstemmed | Systemic and local immune responses to intraocular AAV vector administration in non-human primates |
title_short | Systemic and local immune responses to intraocular AAV vector administration in non-human primates |
title_sort | systemic and local immune responses to intraocular aav vector administration in non-human primates |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844404/ https://www.ncbi.nlm.nih.gov/pubmed/35229004 http://dx.doi.org/10.1016/j.omtm.2022.01.011 |
work_keys_str_mv | AT aildivya systemicandlocalimmuneresponsestointraocularaavvectoradministrationinnonhumanprimates AT renduohao systemicandlocalimmuneresponsestointraocularaavvectoradministrationinnonhumanprimates AT brazhnikovaelena systemicandlocalimmuneresponsestointraocularaavvectoradministrationinnonhumanprimates AT nouveljaillardceline systemicandlocalimmuneresponsestointraocularaavvectoradministrationinnonhumanprimates AT bertinstephane systemicandlocalimmuneresponsestointraocularaavvectoradministrationinnonhumanprimates AT mirashrafiseyedbagher systemicandlocalimmuneresponsestointraocularaavvectoradministrationinnonhumanprimates AT fissonsylvain systemicandlocalimmuneresponsestointraocularaavvectoradministrationinnonhumanprimates AT dalkaradeniz systemicandlocalimmuneresponsestointraocularaavvectoradministrationinnonhumanprimates |