University of Pennsylvania gene therapy pioneer James M. Wilson has been using adeno-associated viral (AAV) vectors in his work for decades. In traditional gene therapy, they act as transporters, carrying the normal version of a gene to a desired cell.

“For someone with genetic blindness, we could deliver a gene to the retina. For someone with muscular dystrophy, we could deliver a gene to the muscle,” says Wilson, director of the Gene Therapy Program and the Orphan Disease Center at the Perelman School of Medicine. “A virus is the most efficient way to do this.”

Viruses typically shuttle their own genes into the cells and cause a person to get sick, sticking around for as long as those cells do. But what if, rather than leading to illness, these vectors instead brought antibodies that could counter SARS-CoV-2?

In collaboration with pharmaceutical company Regeneron, Wilson is working on this approach, which has potential to stop the coronavirus from spreading, as an alternative or supplement to the current vaccines being rolled out. In November, the FDA issued an Emergency Use Authorization (EUA) for a cocktail of two of Regeneron’s lab-made antibodies, casirivimab and imdevimab, to treat COVID-19, with IV infusion as the stipulated treatment method. Though that EUA does not apply to Wilson’s approach, he says he thinks it should make getting future approval for the AAV technique easier.

Penn Today spoke with Wilson about the implications of this research for the current pandemic.

When did you first start using AAV vectors in your gene therapy work?

It came about 10 years ago when I was helping the Gates Foundation develop an approach for preventing HIV. Any attempt to use a traditional vaccine, where you inject a component of the virus to activate the immune system to develop proteins such as antibodies, had been challenging for HIV. Regardless of what you used to immunize—because the virus changed so much—most of it would escape. Once the field realized that, we started to look at other approaches, and it turns out it’s possible in the lab to engineer an antibody that could be effective against many types of HIV.

HIV represents a different type of pandemic than COVID-19. When did you turn to AAV vectors as a potential approach for other kinds of pandemics?

About eight years ago I started thinking about this as a countermeasure for a pandemic. The pandemics that we worry about are primarily transmitted through a respiratory route. If it were direct contact like Ebola virus, it’s not as dangerous because you can avoid touching one another. But if you can’t even be in the same room, that’s a problem.

Respiratory viruses enter our body through the nose and throat. That’s how we get infected. We proposed delivering the vector through a nasal mist or spray to engineer the cells that line the nose and throat to express the antibody. If you can localize this at that site to prevent the virus from going farther, then you don’t need the whole body to express the antibodies.

The antibodies you’re using, called casirivimab and imdevimab, are monoclonal antibodies, meaning they were created in a lab. Can you describe how they work?

Regeneron developed these. They’re highly active and potent against SARS-CoV-2. For treatment, antibodies can be useful. If you’re starting to get sick, you get an infusion or two of the antibodies and then you don’t get sicker. But what do you do with 99% of the population who isn’t sick and never gets sick? Our idea was to use an AAV vector expressing the antibodies to engineer someone’s cells to produce the antibodies. If we do this right, the expression could go on for a long period of time. It’s a one-time vector infusion.

We were able to show in animal models that an AAV sprayed into the nose that expresses an antibody is effective against flu virus that causes respiratory diseases and has the potential to cause a pandemic. The treated animals were completely protected when exposed to flu virus. It’s all about having the right antibody and then engineering a delivery system to have this blockage. We call it a bioshield. It could be a way to stop COVID-19 in its tracks.

Would this approach replace COVID-19 vaccines or be used in conjunction with them?

Theoretically, it could be used in place of a vaccine, but I suspect that traditional vaccines are going to succeed for a lot of people. We see our approach being deployed in individuals for which traditional vaccines may not work as well, patients with diseases that compromise their immune system such as cancer, patients who are on immune-modulating drugs, or even the elderly.

Early data seem to suggest that the elderly have some level of response to the active COVID-19 vaccine, but, like with many other vaccines, older people don’t mount the same immune response as those who are younger. That said, I don’t see any reason why receiving a traditional vaccine would preclude one from using our nasal spray because they do two different things.

The other possibility is that the COVID-19 vaccines we have become less effective because the virus changes. I don’t think this will happen, and I hope it doesn’t, but, if it does, the question becomes, Would the antibodies that Regeneron created become a backup? When we roll out an active vaccine based on a single spike protein into large populations, it creates pressure on the SARS-CoV-2 to change and potentially become resistant. I hope a variant doesn’t emerge, but I do think it behooves us to have some redundancy in place to squelch a potential second wave due to resistant coronaviruses.

What is your projected timeline?

We are conducting one final experiment over the holiday break and in early January before we submit our request to the FDA for clinical trials. We’ve had discussions with the FDA and have already done some of the initial testing, including safety testing in nonhuman primates, as well as preparing to manufacture the product. Conducting this in the Gene Therapy Program is beneficial since we are comfortable with AAV vectors and moving them into clinical trials. We support up to eight traditional AAV gene therapy programs a year, and we have the staff and technology to move pretty quickly.

If we get the go in January, I think our technology could contribute to the global response in eliminating COVID-19. And you have to understand, until we eliminate it globally, we haven’t actually eliminated it.

James M. Wilson is director of the Gene Therapy Program, the Rose H. Weiss Professor and director of the Orphan Disease Center, and a professor of medicine and pediatrics at the Perelman School of Medicine at the University of Pennsylvania.