Self-Complementary AAV (scAAV) Vectors: Enhanced Potency vs. Immune Response

The utilization of self-complementary AAV (scAAV) vectors has been shown to enhance vector potency, resulting in faster and more robust transgene expression. This improvement allows for the administration of lower and safer vector doses. However, when compared to single-stranded AAV (ssAAV) vectors, the use of scAAV genomes has been found to elicit an increased innate immune response to the transgene, primarily due to the activation of the TLR9/MyD88 pathway. Activation of this pathway occurs as a result of the DNA component of the AAV vector, and potentially the production of double-stranded RNA (dsRNA) resulting from the ITR promoter activity of the AAV. These components can act as adjuvants, augmenting the activation of innate immunity in conjunction with other host-specific factors. The presence of dsRNA may contribute to the delayed cellular response observed weeks after vector administration, as it aids in the induction of innate immunity towards AAV.