Foam. That’s what Fred Hutch Cancer Center immunobioengineer Matthias Stephan, MD, PhD, pitched to Katie Fitzgerald when she interviewed for a research technician position in his lab.
“He broached it as, ‘OK, this is a bit strange. We’re looking for someone who's creative or flexible to work on this project,’” said Fitzgerald. “I just thought it was really interesting. I have a biomedical engineering background, so I like problem solving in unique, creative ways.”
Stephan works to make today’s leading-edge — but often prohibitively expensive — cancer therapies cheaper and more easily available. Foam, he thought, could potentially slash the cost of developing and delivering gene therapy.
Buoyed by recent technological advancements like CRISPR-based gene editing, the gene therapy field seems poised to explode. Two gene therapies, using different approaches to treat sickle cell disease, were approved by the U.S. Food and Drug Administration last year. Immune cells genetically engineered to treat cancer were first FDA approved in 2017.
But without other advancements, these and future therapies will remain expensive pipe dreams for most patients.
“What we're addressing is the problem of practicality, the problem of cost and accessibility, and the problem of safety,” Stephan said. “These are the three gaps that are currently limiting the application of gene therapy.”
Foam wasn’t his first out-of-the box idea to help make the latest medical advances more accessible. Stephan’s already co-founded one biotech company to commercialize a nanoparticle-based approach to temporarily reprogramming immune cells inside the body, and developed experimental biomaterial-based strategies to deliver cancer-fighting immune cells to tumors.
Now he’s betting on foam. Earlier this week in the journal Nature Communications, Stephan, Fitzgerald and their team published a study detailing the properties and plus sides of a new, bio-compatible foam they’ve developed to deliver gene therapy.
Stephan co-founded Tidal Therapeutics to help commercialize his immune-cell programming nanoparticles (acquired by Sanofi in 2022). His lab needed a new direction, and inspiration struck one morning as he watched his freshly sprayed shaving foam expand in his palm.
“I thought, ‘Let's explore foam,’” Stephan said. “Maybe we can make a formulation of foam that is not like the foam in in our shaving foam, but something that is biocompatible, to deliver therapeutics.”
The froth had properties that would be attractive in a drug-delivery vehicle. Its volume started small, but puffed up. The foam stayed where it was sprayed, and didn’t slide away. These characteristics could help get a therapeutic into contact with more critical cells while also ensuring that it didn’t slip away.
“Trying new substances or approaches that come from things in everyday life that you wouldn't necessarily associate in medical applications is sometimes a really interesting way to drive down costs and deliver drugs more easily,” Fitzgerald said. “But it was definitely a little bit out of my wheelhouse.”
Foam-as-medical-delivery method isn’t without precedent, Stephan noted. Foam-based delivery already enhances certain applications like delivery of hemorrhoid medication and intra-uterine imaging.
But could foam enhance gene therapy?
To create a bio-compatible foam, Stephan and his team initially took inspiration from the food industry.
“Cocktails, ice cream, yogurt: they know how to make things foamy,” he said.
Stephan Lab members, including staff scientist Sirka Stephan, PhD, started experimenting with ingredients available from the pantry store, he said.
“Importantly, these materials are dead cheap,” Stephan said. “They’re available for pennies. They’re manufactured at large scale, and because they’re already used for pharmaceutical applications — like coating tablets — they’re available pharmaceutical-grade.”
The scientists formulated a solution of methylcellulose (a food binder) and xanthan gum (a food thickener) that, when aerated using two lab syringes, bubbles into an easy-to-apply froth.
But did it have the potential to improve gene therapy?
“We started with a lot of hypotheses in terms of, could foam potentially concentrate our gene therapy, keep it more localized, and help it stay in the tissue where we wanted to adhere?” Fitzgerald said. “My job was to do the experiments to prove the hypotheses.”
Foam has certain properties that make it an attractive drug-delivery vehicle. It’s more than tightly packed air bubbles: In a foam, the bubbles are separated and surrounded by incredibly thin layers of continuous liquid, called lamellae. Active ingredients become highly concentrated in these lamellae, which allows foam to deliver highly concentrated doses of medicine to large areas, even if the total dose is small.
And a stable foam could keep a drug in the right tissue for longer periods, potentially further enhancing efficacy.
Fitzgerald set out to test whether these same properties could enhance gene therapy. There are various types of gene therapies and various strategies to transporting a gene therapy to target cells. Fitzgerald started with lipid nanoparticles containing RNA, similar to RNA-based COVID-19 vaccines. Unlike CRISPR-based gene therapies, these don’t permanently modify a cell’s DNA but can prompt it to temporarily produce new proteins.
“The first thing I did was to encapsulate messenger RNA in lipid nanoparticles and see how these dispersed in foam,” Fitzgerald said. It was her first experience with high-resolution confocal microscopy. “I was looking for almost a lava flow through the lamellae, the channels between the bubbles in the foam.”
Using RNA carrying instructions for making a luminescent protein, Sirka and Matthias Stephan had compared foam delivery of RNA-loaded nanoparticles with the same nanoparticles delivered in a liquid. They tested the two delivery methods on cells growing in perfectly horizontal Petri dishes, as well as on Petri dishes tilted to mimic the less-than-perfect surfaces inside a body.
While liquid delivery resulted in a dim smear, the foam provided enough control to write legible messages that glowed under UV light.
The scientists also tested the same nanoparticles in mice. They found that using the foam improved RNA delivery (the mice’s abdomens glowed more under UV) when injected into the animals’ abdominal cavities. When used as the viral delivery vehicle, foam gave better results at lower doses, while keeping the gene therapy from spreading through the body. (The sickle cell gene therapy, Lyfgenia, uses a viral vector.)
The scientists also found that foam “matures.” Over time, the bubbles grow bigger and push a super-saturated layer of gene therapy vector toward the tissue. This improves penetration of the vector into the tissue.
The proof-of-principle results give Matthias Stephan hope that gene therapy could become cheaper and easier to produce and apply.
“You mix it in syringe just with air and within seconds you have a product that is 10 times more potent,” he said. In theory, slashing the dose would also slash the price and make a gene therapy affordable: “You only need a tiny amount because most of the foam is air and you’re concentrating the small numbers of viral particles or liposomes in the lamellae.”
He, Fitzgerald and Sirka Stephan are exploring more potential applications, including possible applications in cancer. This could include esophageal cancer or ovarian cancer, where a drug-delivery system that contacts all surfaces within the abdominal cavity could help deliver cancer-fighting therapies to lurking tumor cells.
Fitzgerald is also testing the limits of foam: Can it deliver more than nanoparticles, viruses or small-molecule drugs? What about cells?
“It’s a challenge,” she said. “Normally you’re trying to avoid foam, avoid bubbles. But this is all bubbles. So I had to change my mindset.”
Matthias Stephan hopes that the foam will spark inspiration in others.
“Hopefully they will say, ‘We have the vector, it's very expensive, it works. But with that very cheap material — foam — it could become a very potent product,’” he said. “I hope readers will be inspired to think about it and say, ‘Oh, I think I have a great application for this.’”
This work was funded by the Fred Hutch Immunotherapy Initiative and the Bezos Family.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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