New discovery shows how viral vectors release genes in therapy

A research team from The University of Osaka has uncovered the molecular mechanism behind how adeno-associated virus (AAV) vectors release their therapeutic genetic material – an essential step in the effectiveness of gene therapy. Their study, focusing on structural changes in the VP1 protein within AAV capsids, shows that heating induces a transformation in the protein’s N-terminal region, allowing the viral genome to be ejected.

This new insight could significantly improve the design, safety and efficiency of AAV-based gene therapies, which are already being used to treat a range of previously incurable genetic conditions.

The role of VP1 in gene delivery

AAV vectors are commonly used to deliver corrective genes into human cells. However, one of the major gaps in the field has been understanding how these vectors release their cargo once inside the cell.

The Osaka researchers explored the relationship between VP1 structural dynamics and genome ejection using recombinant AAV8 (rAAV8) particles. These were engineered to vary in VP1 content – including samples with only the VP3 protein. Through a combination of temperature ramping and advanced analytical techniques, they carefully monitored the structural transitions occurring within the capsid.

They discovered that when the VP1 N-terminus remained folded, genome release was inhibited. But once the protein unfolded due to heating, the genetic material could be ejected without the capsid breaking apart. This led to the formation of three distinct particle states – genome-containing, genome-tethered, and empty capsids.

Implications for vector design and therapy safety

The molecular-level understanding gained from this study marks a turning point in the field. It provides a clear framework for enhancing AAV vector performance and offers new benchmarks for vector quality control, thermal stability and storage protocols.

“Gene therapy holds great promise as an innovative treatment for previously incurable diseases, but the production and quality control of vectors present significant challenges,” said Senior Author Susumu Uchiyama. “Through meticulous analysis by our students and young faculty members, we have key indicators for stable AAV gene therapy vector production and storage, paving the way for delivering these innovative treatments to patients sooner.”

A roadmap for future Gene Therapy Innovations

The discovery of VP1-mediated genome release adds a critical piece to the puzzle of how AAV vector’s function. It opens doors to engineering more predictable, controlled and effective gene delivery systems – pushing gene therapy closer to widespread clinical use.

As the demand for gene therapies grows, the need for stable, safe and efficient delivery vehicles becomes ever more important. This research not only addresses that need but also empowers future innovations by setting new standards for AAV vector performance and design.