Enhanced Transgene Expression and Innate Immune Response with Self-Complementary AAV Vectors

The utilization of self-complementary AAV (scAAV) vectors enhances the efficacy of the vector by facilitating faster and more robust expression of the transgene. This, in turn, allows for the administration of lower and safer vector doses. However, when compared to the single-stranded AAV (ssAAV) vector, the use of scAAV genome leads to an augmented innate immune response towards the transgene, primarily due to the activation of the TLR9/MyD88 pathway. The DNA component of the AAV vector, as well as the potential production of dsRNA resulting from the ITR promoter activity, can function as an adjuvant, activating innate immunity alongside other host-specific factors. The presence of dsRNA may contribute to the induction of innate immunity to AAV, potentially explaining the delayed cellular response observed in some cases, which can occur several weeks following vector administration.