Adaptive immune responses to Adeno-Associated Virus (AAV) vector-mediated gene transfer

TL;DRAbstract

Adeno-Associated Virus (AAV) vectors are promising gene transfer vehicles that have been tested extensively in preclinical animal models and human clinical trials. However, immune responses to the AAV vectors remain a concern for safety and for sustained therapeutic transgene expression. This thesis attempts to investigate adaptive immune responses to the transgene product as well as the capsid of different DNA configurations of AAV vectors: self-complementary AAV vectors, single-stranded AAV vectors, and empty AAV vectors. The results show that self-complementary AAV vectors induce elevated CD8+ T and B cell responses to the transgene product compared to single-stranded AAV vectors, across multiple serotypes including AAV2, 7 and 8. T cell responses to the transgene product carried by self-complementary AAV vectors demonstrate impaired functionality as well as gradual loss of functions with upregulation of PD-1 expression, indicative of T cell exhaustion. The B cell response to the tr

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