Adeno-associated virus (AAV) has earned significant attention as a safe and efficient gene therapy tool. AAV has been used in over 100 clinical trials to treat a variety of human diseases. However, non-specific targeting to diseased cells and activation of the host immune response hinder its therapeutic efficacy. To address these challenges, genetic modification of the AAV capsid can lead to an improved gene delivery platform. Therefore, capsid-engineering strategies may be necessary to develop optimized vectors for clinical progress.
This present work reveals design rules governed by amino acid properties for engineered AAV to become activated by upregulated proteolytic biomarkers in diseased sites. AAV constructs with varying chemical properties were synthesized and characterized for functional behavior. In parallel, a Nature-inspired strategy was employed to create an immune-evasive AAV vector. A panel of AAV vectors with inserted stealth peptides in the AAV capsid was generated to study immune cell uptake. Finally, to gain a better understanding of AAV intracellular trafficking, we found several amino acid residues that are necessary for viral infectivity. The ultimate goal for my research contributions is to develop and to advance AAV vectors for future clinical applications.