TR: Why can AAV vectors evade the immune system, while adenovirus vectors trigger immune reactions?
JW: AAV vectors do two things: they can get into a liver or heart cell without activating a type of T cell involved in the immune response, sort of like a stealth plane. These vectors can also activate a type of T cell that suppresses the immune response. We don’t know why AAV vectors do this or why they are in such contrast to the adenovirus vector. Maybe this is how the native virus evolved to escape immune detection.
TR: Do AAV vectors have a downside?
JW: We found that the prototype vector, known as AAV2, was not efficient enough. It could get into a few cells, but it was not efficient enough to have a therapeutic effect.
TR: So how do you make these vectors more efficient?
JW: There are two possibilities. One is to reengineer the vector, but it’s very difficult to reengineer a biological organism that has evolved over time. A virus is not like a small molecule drug such as aspirin. It’s a biological particle, so it’s much more difficult to tinker with.
Fortunately, evolution has generated a diversity of viruses. We screened monkeys and humans for lingering adenovirus-associated viral infection. Adenovirus-associated viruses infect humans and primates. No one knows what the virus does, what the infection looks like or whether it hurts or helps you. We discovered that 40 percent of human livers have persistent infections, and we identified over 100 new subtypes.
Now we are looking at the properties of the vectors and how well they can be transferred to different organs. We found that a variation of a vector called AAV9 can efficiently transfer genes to the heart.
TR: Have AAV vectors been tested in human trials? How safe are they?
JW: Yes. AAV2 has been tested for cystic fibrosis, muscular dystrophy, neurological disease, and hemophilia. Two patients in the hemophilia trial developed liver inflammation, although they did recover. Other than that, there have been no safety issues.
Since then, we’ve tried to determine if the new AAV vectors will have the same response. We don’t think they will – we think we’ve figured out what happened in those patients and how to get around it. [Wilson has a paper on this topic currently under review at a scientific journal.]
TR: Are the new vectors being tests in clinical trials?
JW: Penn [the University of Pennsylvania] licensed the vectors to GlaxoSmithKline [a pharmaceutical company headquartered in the United Kingdom.] They are pursuing various applications, such as treatments for lung, heart, and liver disease, although nothing has yet been tested in humans.
TR: How will scientists decide which vectors are the best to move forward into clinical trials?
JW: That is something we still need to decide. Will large animal studies be required? These studies are very resource intensive. We need to identify good animal models that will predict efficacy in humans.