Gene therapy, with its potential to alter genes inside a patient’s cells, could be one of our most powerful tools in medicine—it holds the promise of “one-and-done” cures for genetic diseases. When it comes to these diseases, we often know precisely the genetic payloads we want to deliver, but don’t always have the right vehicles to deliver them into the relevant cells in the body. Adeno-associated virus (AAV), considered to be largely harmless to humans, is the primary workhorse vehicle (vector) we use today to deliver therapeutic genes in the body. But AAV has its limitations: it may not deliver enough of its genetic payload to the right cells, it’s difficult to manufacture, it can have serious safety issues at very high doses, and many patients are not candidates for AAV-based therapies because they have pre-existing immunity to certain AAVs. We currently have just two approved gene therapies, but the industry hopes to have as many as 10-20 cell and gene therapy approvals per year by the end of 2025. Gene therapy has the potential to treat—and even cure—thousands of devastating diseases. Can AAVs deliver? 

AAVs’ therapeutic potential was originally observed over 20 years ago. Since then, scientists have pursued multiple approaches to discover, evolve, or design novel AAVs with enhanced properties and characteristics. Can we find an AAV that specifically targets, say, the central nervous system in order to treat neurodegenerative diseases? Or design an AAV that’s easier to manufacture? It’s a hard mountain to climb. AAV capsids (shells) are delicate, complex 20-sided structures. When it comes to manipulating them in order to improve them, one false step can result in a precipitous “fall” that breaks the capsid. And even if you can make progress on optimizing one property (like tissue-specific targeting), it often comes at the significant expense of others (like manufacturability and immunogenicity). Which is why traditional approaches—directed evolution or rational design, or even the hope of discovering other naturally occurring AAVs—have rarely yielded improved capsids. A more powerful approach is needed to escape the limitations of natural AAVs and fully realize the promise of gene therapy.