Systemic and local immune responses to intraocular AAV vector administration in non-human primates - Approches génétiques intégrées et nouvelles thérapies pour les maladies rares Accéder directement au contenu
Article Dans Une Revue Molecular Therapy - Methods and Clinical Development Année : 2022

Systemic and local immune responses to intraocular AAV vector administration in non-human primates

Résumé

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 preexistence 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.
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Dates et versions

hal-03602826 , version 1 (09-03-2022)

Identifiants

Citer

Divya Ail, Duohao Ren, Elena Brazhnikova, Céline Nouvel-Jaillard, Stephane Bertin, et al.. Systemic and local immune responses to intraocular AAV vector administration in non-human primates. Molecular Therapy - Methods and Clinical Development, 2022, 24, pp.306 - 316. ⟨10.1016/j.omtm.2022.01.011⟩. ⟨hal-03602826⟩
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