Getting gene therapies into the brain is hard. The blood-brain barrier blocks most delivery vehicles. A study in Cell Reports engineers a new viral vector that achieves 100-fold better brain delivery by targeting a specific receptor on blood-brain barrier cells.
The Delivery Problem
Adeno-associated viruses (AAVs) are the workhorse of gene therapy - they're safe and can deliver therapeutic genes to cells. But natural AAV serotypes poorly cross the blood-brain barrier, limiting their utility for neurological diseases.
Some engineered AAVs work well in mice or monkeys but don't translate to humans due to species differences.
Targeting Human Carbonic Anhydrase IV
The researchers took a new approach: they engineered AAVs to specifically target human carbonic anhydrase IV (CA-IV), a receptor recently identified as mediating transcytosis across the blood-brain barrier.
By selecting AAV variants that bind human CA-IV, they could develop vectors optimized for human brain delivery from the start.
The Screening Strategy
First, in vitro selection identified AAVs that bound human CA-IV. Then, the top candidates were tested in mice engineered to express human CA-IV in their brain blood vessels.
Interestingly, some variants that performed best in living mice were not the top performers in the test tube - emphasizing the importance of in vivo validation.
100-Fold Improvement
The top variant, AAV-hCA4-IV77, achieved 100-fold greater brain transduction than AAV9, the current standard. It robustly labeled neurons and astrocytes across brain regions.
This approach - designing for human receptors from the start - could accelerate development of gene therapies for neurological diseases.
Reference: Bhade S, et al. (2025). AAVs targeting human carbonic anhydrase IV enhance gene delivery to the brain. Cell Reports. doi: 10.1016/j.celrep.2025.116419 | PMID: 41175373
Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.