Stoddard, a structural biologist, soon began studying the proteins and over the last decade has advanced the world’s understanding of the form and function of homing endonucleases. As one of the first scientists to reveal the atomic structures of homing endonucleases and, later, to demonstrate they could be engineered to home in on human genes, Stoddard is poised to exploit their capabilities to treat life-threatening disease through a technique known as targeted gene correction.
Collaborating with the Center’s physician-scientists, Stoddard is starting with chronic blood-borne viral infections, including HIV and hepatitis B, because the blood stem cells are easily accessible in the bloodstream. That could be just the beginning, though. "There’s no end to the potential application of homing endonucleases to treat human disease," Stoddard said.
"Whether it’s my particular approach or not, there’s no question that [targeted gene correction] is going to happen before my career is over," he said.
Although still in the developmental stage, targeted gene correction represents a giant step forward from existing gene therapy. The current approach involves introducing a corrected version of a defective — and disease-causing — gene with the hope it assumes the role normally performed by the defective gene. The problem is that the corrected gene doesn’t always find its way into a safe or useful location in a patient’s DNA — a drawback that limits the therapeutic benefit and often causes harmful side effects.
Targeted gene correction involves directly repairing the disease-causing gene — an approach that promises more predictable results without harmful side effects. The key is to deliver the therapy to precisely the right gene. Homing endonucleases can do just that.
Occurring naturally only in microbes such as algae, fungi and bacteria, homing endonucleases perform no particular function on their own. "They just hitch a ride in the DNA of their host organism," Stoddard said.
The magic is that they can be redesigned to recognize specific human genes and carry out helpful chemical processes. To prove the concept is viable, Stoddard used a redesigned homing endonuclease to modify a gene thought to be associated with Parkinson’s disease.
Stoddard said it’s only a matter of time before targeted gene correction becomes a reality in the clinic. "Whether it’s my particular approach or not, there’s no question that it’s going to happen before my career is over," he said. "And that makes this a very exciting field."