AAVDiff: Experimental Validation of Enhanced Viability and Diversity in Recombinant Adeno-Associated Virus (AAV) Capsids through Diffusion Generation
This work addresses limitations in gene therapy by enhancing capsid design, though it appears incremental as it builds on existing diffusion methods applied to a specific biological domain.
The researchers tackled the challenge of designing improved recombinant adeno-associated virus (rAAV) capsids for gene therapy by developing a diffusion model to generate viable capsid sequences, resulting in the generation of 38,000 diverse AAV2 sequences and successful transfer to AAV9 with up to 9 mutations.
Recombinant adeno-associated virus (rAAV) vectors have revolutionized gene therapy, but their broad tropism and suboptimal transduction efficiency limit their clinical applications. To overcome these limitations, researchers have focused on designing and screening capsid libraries to identify improved vectors. However, the large sequence space and limited resources present challenges in identifying viable capsid variants. In this study, we propose an end-to-end diffusion model to generate capsid sequences with enhanced viability. Using publicly available AAV2 data, we generated 38,000 diverse AAV2 viral protein (VP) sequences, and evaluated 8,000 for viral selection. The results attested the superiority of our model compared to traditional methods. Additionally, in the absence of AAV9 capsid data, apart from one wild-type sequence, we used the same model to directly generate a number of viable sequences with up to 9 mutations. we transferred the remaining 30,000 samples to the AAV9 domain. Furthermore, we conducted mutagenesis on AAV9 VP hypervariable regions VI and V, contributing to the continuous improvement of the AAV9 VP sequence. This research represents a significant advancement in the design and functional validation of rAAV vectors, offering innovative solutions to enhance specificity and transduction efficiency in gene therapy applications.