Novel AAV capsid variants for CNS-targeted gene therapies
Unmet Need
The development of effective gene therapies for central nervous system (CNS) diseases faces a critical bottleneck: current adeno-associated virus (AAV) vectors lack sufficient transduction efficiency and specificity for human brain cells. Standard AAV serotypes (e.g., AAV8, AAV9) show limited uptake and gene expression in the human CNS, necessitating high doses that increase safety risks and immunogenicity. Furthermore, capsids evolved in animal models often fail to translate effectively to human tissues. To realize transformative gene therapies for neurodegenerative and neurodevelopmental disorders, there is an urgent need for AAV vectors that provide efficient, targeted gene delivery to the human brain—validated in systems predictive of human clinical outcomes.
Technology
Duke inventors have developed a novel AAV capsid platform engineered directly in live human brain tissue. This is intended to improve transduction efficiency and tropism of CNS-targeted gene therapies. Specifically, by evolving capsid libraries on human cortical slice cultures, the inventors identified capsid variants with significantly improved tropism and transduction efficiency in human neurons and glia. These capsids achieved up to 12-fold higher gene expression than standard AAV8 and AAV9 in ex vivo human brain slices. Functional improvements were also confirmed by in vivo mouse studies, where neonatal intracerebroventricular injection resulted in greater and more widespread brain transduction compared to standard AAV8/9.
Advantages
- Up to 12x greater gene expression in human brain slices than AAV8/9.
- Improved targeting of neurons and glia supports efficient, lower-dose CNS gene delivery.
- Engineered in human brain tissue for enhanced translational value.