Self-Complementary AAV (scAAV) Vectors: Enhanced Potency But Increased Innate Immune Response

The utilization of self-complementary AAV (scAAV) vectors has gained traction in recent years due to their ability to enhance vector potency, resulting in faster and more robust transgene expression. This advancement allows for the administration of lower and safer vector doses. However, it should be noted that the use of scAAV genomes triggers an augmented innate immune response to the transgene compared to single-stranded AAV (ssAAV) vectors. This response is primarily attributed to the activation of the TLR9/MyD88 pathway. The DNA component of the AAV vector, along with the potential production of double-stranded RNA (dsRNA) caused by the ITR promoter activity, can act as an adjuvant, thereby stimulating innate immunity in conjunction with other host-specific factors. The presence of dsRNA may play a role in inducing innate immunity to AAV, which could potentially explain the delayed cellular response observed weeks after vector administration.