Structural Studies of Parvoviridae Capsid Assembly and Evolution: Implications for Novel AAV Vector Design

Heather A Noriega ¹ Qizhao Wang ² Daozhan Yu ² Xiang Simon Wang ^1*

• ¹ Howard University, Washington, D.C., United States
• ² AAVnerGene Inc., Rockville, MD, United States

Adeno-associated virus (AAV) vectors have emerged as powerful tools in gene therapy, potentially treating various genetic disorders. Engineering the AAV capsids through computational methods enables the customization of these vectors to enhance their effectiveness and safety. This engineering allows for the development of gene therapies that are not only more efficient but also personalized to unique genetic profiles. When developing, it is essential to understand the structural biology and the vast techniques used to guide vector designs. This review covers the fundamental biology of the Parvoviridae capsids, focusing on modern structural study techniques, including a) Cryo-electron microscopy and X-ray Crystallography studies and b) Comparative analysis of capsid structures across different Parvoviridae species. Along with the structure and evolution of the Parvoviridae capsids, computational methods have provided significant insights into the design of novel AAV vector techniques, which include a) Structure-guided design of AAV capsids with improved properties, b) Directed Evolution of AAV capsids for specific applications, and c) Computational prediction of AAV capsid-receptor interactions. Further discussion addressed the ongoing challenges in the AAV vector design and proposed future directions for exploring enhanced computational tools, such as artificial intelligence/machine learning and deep learning.