{"id":"doi:10.1186/1479-5876-12-25","kind":"article","title":"Role of the vector genome and underlying factor IX mutation in immune responses to AAV gene therapy for hemophilia B","authors":["Rogers GL","Martino AT","Zolotukhin I","Ertl HC","Herzog RW"],"author_count":5,"year":2014,"published":"2014-01-25","venue":"Journal of translational medicine","cited_by":36,"doi":"10.1186/1479-5876-12-25","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1186/1479-5876-12-25","archive_url":"https://space-kitty.com/papers/doi:10.1186/1479-5876-12-25","updated":null,"pmid":"24460861","pmcid":"PMC3904690","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC3904690/pdf","abstract":"Background Self-complementary adeno-associated virus (scAAV) vectors have become a desirable vector for therapeutic gene transfer due to their ability to produce greater levels of transgene than single-stranded AAV (ssAAV). However, recent reports have suggested that scAAV vectors are more immunogenic than ssAAV. In this study, we investigated the effects of a self-complementary genome during gene therapy with a therapeutic protein, human factor IX (hF.IX). Methods Hemophilia B mice were injected intramuscularly with ss or scAAV1 vectors expressing hF.IX. The outcome of gene transfer was assessed, including transgene expression as well as antibody and CD8⁺ T cell responses to hF.IX. Results Self-complementary AAV1 vectors induced similar antibody responses (which eliminated systemic hF.IX expression) but stronger CD8⁺ T cell responses to hF.IX relative to ssAAV1 in mice with F9 gene deletion. As a result, hF.IX-expressing muscle fibers were effectively eliminated in scAAV-treated mice. In contrast, mice with F9 nonsense mutation (late stop codon) lacked antibody or T cell responses, thus showing long-term expression regardless of the vector genome. Conclusions The nature of the AAV genome can impact the CD8⁺ T cell response to the therapeutic transgene product. In mice with endogenous hF.IX expression, however, this enhanced immunogenicity did not break tolerance to hF.IX, suggesting that the underlying mutation is a more important risk factor for transgene-specific immunity than the molecular form of the AAV genome.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Role of the vector genome and underlying factor IX mutation in immune responses to AAV gene therapy for hemophilia B\" by Rogers GL, Martino AT, Zolotukhin I et al., https://doi.org/10.1186/1479-5876-12-25, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-cell-therapy","name":"Gene & Cell Therapy","domain_slug":"medicine"}],"cited_in_dossiers":[]}