# Role of the vector genome and underlying factor IX mutation in immune responses to AAV gene therapy for hemophilia B

Article · Rogers GL, Martino AT, Zolotukhin I, Ertl HC, Herzog RW

- Archive id: doi:10.1186/1479-5876-12-25
- Published: 2014-01-25
- Venue: Journal of translational medicine
- DOI: https://doi.org/10.1186/1479-5876-12-25
- PMID: 24460861
- PMCID: PMC3904690
- Citations: 36
- Source URL: https://doi.org/10.1186/1479-5876-12-25
- PDF: https://europepmc.org/articles/PMC3904690/pdf
- Provenance: europepmc

## 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 reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Gene & Cell Therapy](https://space-kitty.com/topics/gene-cell-therapy)

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