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Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase

Immune responses to human non-self transgenes can present challenges in preclinical studies of adeno-associated virus (AAV) gene therapy candidates in nonhuman primates. Although anti-transgene immune responses are usually mild and non-adverse, they can confound pharmacological readouts and complica...

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Autores principales: Hordeaux, Juliette, Ramezani, Ali, Tuske, Steve, Mehta, Nickita, Song, Chunjuan, Lynch, Anna, Lupino, Katherine, Chichester, Jessica A., Buza, Elizabeth L., Dyer, Cecilia, Yu, Hongwei, Bell, Peter, Weimer, Jill M., Do, Hung, Wilson, James M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10073725/
https://www.ncbi.nlm.nih.gov/pubmed/37033976
http://dx.doi.org/10.3389/fimmu.2023.1094279
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author Hordeaux, Juliette
Ramezani, Ali
Tuske, Steve
Mehta, Nickita
Song, Chunjuan
Lynch, Anna
Lupino, Katherine
Chichester, Jessica A.
Buza, Elizabeth L.
Dyer, Cecilia
Yu, Hongwei
Bell, Peter
Weimer, Jill M.
Do, Hung
Wilson, James M.
author_facet Hordeaux, Juliette
Ramezani, Ali
Tuske, Steve
Mehta, Nickita
Song, Chunjuan
Lynch, Anna
Lupino, Katherine
Chichester, Jessica A.
Buza, Elizabeth L.
Dyer, Cecilia
Yu, Hongwei
Bell, Peter
Weimer, Jill M.
Do, Hung
Wilson, James M.
author_sort Hordeaux, Juliette
collection PubMed
description Immune responses to human non-self transgenes can present challenges in preclinical studies of adeno-associated virus (AAV) gene therapy candidates in nonhuman primates. Although anti-transgene immune responses are usually mild and non-adverse, they can confound pharmacological readouts and complicate translation of results between species. We developed a gene therapy candidate for Pompe disease consisting of AAVhu68, a clade F AAV closely related to AAV9, that expresses an engineered human acid-alpha glucosidase (hGAA) tagged with an insulin-like growth factor 2 variant (vIGF2) peptide for enhanced cell uptake. Rhesus macaques were administered an intravenous dose of 1x10(13) genome copies (GC)/kg, 5x10(13) GC/kg, or 1 x 10(14) GC/kg of AAVhu68.vIGF2.hGAA. Some unusually severe adaptive immune responses to hGAA presented, albeit with a high degree of variability between animals. Anti-hGAA responses ranged from absent to severe cytotoxic T-cell-mediated myocarditis with elevated troponin I levels. Cardiac toxicity was not dose dependent and affected five out of eleven animals. Upon further investigation, we identified an association between toxicity and a major histocompatibility complex class I haplotype (Mamu-A002.01) in three of these animals. An immunodominant peptide located in the C-terminal region of hGAA was subsequently identified via enzyme-linked immunospot epitope mapping. Another notable observation in this preclinical safety study cohort pertained to the achievement of robust and safe gene transfer upon intravenous administration of 5x10(13) GC/kg in one animal with a low pre-existing neutralizing anti-capsid antibodies titer (1:20). Collectively, these findings may have significant implications for gene therapy inclusion criteria.
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spelling pubmed-100737252023-04-06 Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase Hordeaux, Juliette Ramezani, Ali Tuske, Steve Mehta, Nickita Song, Chunjuan Lynch, Anna Lupino, Katherine Chichester, Jessica A. Buza, Elizabeth L. Dyer, Cecilia Yu, Hongwei Bell, Peter Weimer, Jill M. Do, Hung Wilson, James M. Front Immunol Immunology Immune responses to human non-self transgenes can present challenges in preclinical studies of adeno-associated virus (AAV) gene therapy candidates in nonhuman primates. Although anti-transgene immune responses are usually mild and non-adverse, they can confound pharmacological readouts and complicate translation of results between species. We developed a gene therapy candidate for Pompe disease consisting of AAVhu68, a clade F AAV closely related to AAV9, that expresses an engineered human acid-alpha glucosidase (hGAA) tagged with an insulin-like growth factor 2 variant (vIGF2) peptide for enhanced cell uptake. Rhesus macaques were administered an intravenous dose of 1x10(13) genome copies (GC)/kg, 5x10(13) GC/kg, or 1 x 10(14) GC/kg of AAVhu68.vIGF2.hGAA. Some unusually severe adaptive immune responses to hGAA presented, albeit with a high degree of variability between animals. Anti-hGAA responses ranged from absent to severe cytotoxic T-cell-mediated myocarditis with elevated troponin I levels. Cardiac toxicity was not dose dependent and affected five out of eleven animals. Upon further investigation, we identified an association between toxicity and a major histocompatibility complex class I haplotype (Mamu-A002.01) in three of these animals. An immunodominant peptide located in the C-terminal region of hGAA was subsequently identified via enzyme-linked immunospot epitope mapping. Another notable observation in this preclinical safety study cohort pertained to the achievement of robust and safe gene transfer upon intravenous administration of 5x10(13) GC/kg in one animal with a low pre-existing neutralizing anti-capsid antibodies titer (1:20). Collectively, these findings may have significant implications for gene therapy inclusion criteria. Frontiers Media S.A. 2023-03-22 /pmc/articles/PMC10073725/ /pubmed/37033976 http://dx.doi.org/10.3389/fimmu.2023.1094279 Text en Copyright © 2023 Hordeaux, Ramezani, Tuske, Mehta, Song, Lynch, Lupino, Chichester, Buza, Dyer, Yu, Bell, Weimer, Do and Wilson https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Hordeaux, Juliette
Ramezani, Ali
Tuske, Steve
Mehta, Nickita
Song, Chunjuan
Lynch, Anna
Lupino, Katherine
Chichester, Jessica A.
Buza, Elizabeth L.
Dyer, Cecilia
Yu, Hongwei
Bell, Peter
Weimer, Jill M.
Do, Hung
Wilson, James M.
Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase
title Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase
title_full Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase
title_fullStr Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase
title_full_unstemmed Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase
title_short Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase
title_sort immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10073725/
https://www.ncbi.nlm.nih.gov/pubmed/37033976
http://dx.doi.org/10.3389/fimmu.2023.1094279
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