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Bing, So Jin; Justesen, Sune; Wu, Wells W.; Sajib, Abdul Mohin; Warrington, Stephanee; Baer, Alan; Thorgrimsen, Stephan; Shen, Rong-Fong; Mazor, Ronit
Molecular therapy. Methods & clinical development, 03/2022, Letnik: 24, Številka: CJournal Article
Despite the high safety profile demonstrated in clinical trials, the immunogenicity of adeno-associated virus (AAV)-mediated gene therapy remains a major hurdle. Specifically, T-cell-mediated immune responses to AAV vectors are related to loss of efficacy and potential liver toxicities. As post-translational modifications in T cell epitopes have the potential to affect immune reactions, the cellular immune responses to peptides derived from spontaneously deamidated AAV were investigated. Here, we report that highly deamidated sites in AAV9 contain CD4 T cell epitopes with a Th1 cytokine pattern in multiple human donors with diverse human leukocyte antigen (HLA) backgrounds. Furthermore, some peripheral blood mononuclear cell (PBMC) samples demonstrated differential T cell activation to deamidated or non-deamidated epitopes. Also, in vitro and in silico HLA binding assays showed differential binding to the deamidated or non-deamidated peptides in some HLA alleles. This study provides critical attributes to vector-immune-mediated responses, as AAV deamidation can impact the immunogenicity, safety, and efficacy of AAV-mediated gene therapy in some patients. Display omitted Deamidation of AAV vectors occurs after long-term storage. Here, we show that deamidation of AAV-derived peptides can increase T cell immunogenicity in some individuals and decrease it in others. This subject-to-subject variability is associated with differential binding to some HLA molecules.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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