التفاصيل البيبلوغرافية
| العنوان: |
DataSheet_1_Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase.pdf |
| المؤلفون: |
Juliette Hordeaux, Ali Ramezani, Steve Tuske, Nickita Mehta, Chunjuan Song, Anna Lynch, Katherine Lupino, Jessica A. Chichester, Elizabeth L. Buza, Cecilia Dyer, Hongwei Yu, Peter Bell, Jill M. Weimer, Hung Do, James M. Wilson |
| سنة النشر: |
2023 |
| المجموعة: |
Frontiers: Figshare |
| مصطلحات موضوعية: |
Immunology, Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies), Autoimmunity, Cellular Immunology, Humoural Immunology and Immunochemistry, Immunogenetics (incl. Genetic Immunology), Innate Immunity, Transplantation Immunology, Tumour Immunology, Immunology not elsewhere classified, Genetic Immunology, Animal Immunology, Veterinary Immunology, AAV, toxicity, cytotoxic, T cell, Pompe disease |
| الوصف: |
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. |
| نوع الوثيقة: |
dataset |
| اللغة: |
unknown |
| العلاقة: |
https://figshare.com/articles/dataset/DataSheet_1_Immune_transgene-dependent_myocarditis_in_macaques_after_systemic_administration_of_adeno-associated_virus_expressing_human_acid_alpha-glucosidase_pdf/22314520Test |
| DOI: |
10.3389/fimmu.2023.1094279.s001 |
| الإتاحة: |
https://doi.org/10.3389/fimmu.2023.1094279.s001Test
https://figshare.com/articles/dataset/DataSheet_1_Immune_transgene-dependent_myocarditis_in_macaques_after_systemic_administration_of_adeno-associated_virus_expressing_human_acid_alpha-glucosidase_pdf/22314520Test |
| حقوق: |
CC BY 4.0 |
| رقم الانضمام: |
edsbas.EFC1677E |
| قاعدة البيانات: |
BASE |
