The following is a condensed and edited interview with Jim Wilson, geneticist, University of Pennsylvania.
How does gene therapy work?
A new gene is inserted into a cell that either corrects a function or imposes on the cell a new function. Genes are unwieldy, since they’re large, highly charged, and need to get to the right cells. If done properly, the gene will take up residence in the cell and persist for the life of the cell, setting the stage for a cure. Viruses are co-opted as gene-delivery vehicles—also called vectors—by exchanging their disease-causing genes with therapeutic genes.
When I first learned of gene therapy, it just seemed so elegant and simple. It also had the potential for treating diseases at its root. It turned out it was much, much more complicated than I had envisioned.
In 1999 you were running a gene therapy trial at the University of Pennsylvania. Tell me about Jesse.
We had advanced the trial through various different stages, doses. The second research subject for the highest dose was Jesse Gelsinger. When the vector was administered to him, he mounted what appeared to be a much more severe and much more rapid-onset immune response than anything we had seen before. He ultimately died from the consequences of that immune reaction.
That was a catalytic moment for the entire field.
The biotech industry had become very invested in this and right around that time the dot-com fiasco happened, and there was an exodus from biotech, including gene therapy. The support just vanished.
Jesse’s death sparked investigations and a huge backlash. Why did you keep going?
I was incredibly disappointed that what had happened had, first of all, led to the death of a young man, but also had set the field back. That was never my intention. But this incident exposed what the deficiencies were.
And now gene therapy is back, with safer viral vectors that you’ve been working on for more than a decade. Which companies today have licensed your vectors?
Regenxbio, Dimension Therapeutics, Voyager Therapeutics, AveXis, Audentes Therapeutics, and now Biogen and J&J.
Where else in the body is gene therapy being tried?
So, there is this vector that we discovered, AAV9, which has this almost mysterious property of getting across the blood-brain barrier and distributing broadly within the brain. There is so much unmet need, so much morbidity and mortality and disability in neurologic genetic diseases that if we can crack this nut, it’s going to be huge.
Are you using gene therapy in ways that you couldn’t have imagined when you started?
We developed [a program] to engineer cells of the airway, the nose and the throat, to express antibodies against virtually all strains of influenza. We’ve exposed mice and ferrets to a lethal challenge of influenza, including the strain that came out of the 1918 pandemic, and we have funding through the Department of Defense to take this into the clinic. Our view would be to stockpile it, have it ready if there was a pandemic. If it worked against everything back to 1918, you would presume it’s going to work against everything that would happen going forward.
When do you start human trials for that?
Within the year.
Gene therapy is expected to be very expensive, since they are intended to be a one-time treatment that’s curative.
I’ve been worried about this for a long time. But if we in the field can deliver a transformative medicine that cures patients or prevents kids from dying and being disabled, then we as a society will figure out a way to get these treatments to those who are needing them. And if we don’t, shame on us.
What advice do you have for young scientists?
You have to be patient, and one needs to be very humble. Biology is complicated, clinical trials take time. There is nothing—no amount of money, no amount of determination or whatever else that can hasten that. I think that one of the issues that got this field into trouble was the expectations that were unrealistic. If you’re not humble, you’ll be arrogant, and you’re not going to be a good scientist. You’re going to make mistakes.