Adeno-associated viruses are the most clinically validated delivery vectors for in vivo gene therapy, with multiple approved products and hundreds of ongoing clinical trials. AAVs are small, non-enveloped viruses with a single-stranded DNA genome of approximately 4.7 kilobases. Different AAV serotypes exhibit distinct tissue tropisms, enabling targeting of specific organs including liver (AAV8, AAV9), muscle (AAV9), retina (AAV2), and central nervous system (AAV9, AAVrh10). This natural tissue selectivity, combined with a favorable safety profile, has made AAV the vector of choice for most in vivo gene therapy programs.
The engineering of novel AAV capsids has become a major area of innovation. Companies like Dyno Therapeutics, co-founded by George Church, use machine learning and directed evolution to design synthetic AAV capsids with improved tissue specificity, enhanced transduction efficiency, and reduced immunogenicity. Regenxbio holds an extensive patent portfolio covering natural AAV serotypes and engineered variants. 4D Molecular Therapeutics develops optimized AAV vectors through systematic capsid engineering for ophthalmology and cardiology applications. These efforts aim to overcome the limitations of natural AAV serotypes, including pre-existing immunity in patients previously exposed to wild-type AAV.
Manufacturing AAV at sufficient quality and scale remains a significant industry challenge. The packaging capacity limit of approximately 4.7 kilobases restricts the size of therapeutic genes that can be delivered, requiring dual-vector strategies or mini-gene approaches for larger payloads. Production yields in mammalian cell culture systems are often low, driving up costs. Forge Biologics, Catalent, and other CDMOs are investing in large-scale AAV manufacturing capabilities using both adherent and suspension cell platforms. Emerging production methods including baculovirus-insect cell systems and stable producer cell lines aim to improve scalability and reduce the cost of goods for AAV-based therapies.