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

摘要: Background: Self-complementary adeno-associated virus (scAAV) vectors have become a desirable vector for therapeutic gene transfer due to their ability produce greater levels of transgene than single-stranded AAV (ssAAV). However, recent reports suggested that scAAV are more immunogenic ssAAV. In this study, we investigated the effects self-complementary genome during therapy with protein, human factor IX (hF.IX). Methods: Hemophilia B mice were injected intramuscularly ss or scAAV1 expressing hF.IX. The outcome was assessed, including expression as well antibody and CD8 + T cell responses Results: AAV1 induced similar (which eliminated systemic hF.IX expression) but stronger relative ssAAV1 in F9 deletion. As result, hF.IX-expressing muscle fibers effectively scAAV-treated mice. contrast, nonsense mutation (late stop codon) lacked responses, thus showing long-term regardless genome. Conclusions: nature can impact response product. endogenous expression, however, enhanced immunogenicity did not break tolerance hF.IX, suggesting underlying is important risk transgene-specific immunity molecular form