There are as many food allergies as there are things to eat. By some accounts, more than one in ten Americans is allergic to a common food, often eggs, peanuts, or fish. Despite being prevalent and often deadly, the medical standard of care for food allergies is to advise patients to simply avoid those foods.
The sheer dearth of better treatment options might have inspired David Markusic, an immunologist at Indiana University, to try something different — if he had set out to study food allergies in the first place. Markusic studies hemophilia B, but he and his collaborators recently published a paper about a gene therapy that abolishes a food allergy in mice in the journal Molecular Therapy (1).
Heomphilia B is a clotting disorder where a mutation in the gene for coagulation protein factor IX leads to bruising and bleeding. Markusic set out to develop a gene therapy that restores a functional factor IX gene. In the course of testing the therapy, however, some mice developed allergic reactions to factor IX protein that were so severe that they died within minutes of treatment. Humans with hemophilia often use enzyme replacement treatments, and three to five percent develop allergies as well.
That piqued Markusic’s curiosity. He began to wonder how he could prevent immune responses against the proteins he delivered to hemophiliac mice.
“We inadvertently found that we could prevent the factor IX allergic responses using gene therapy. Based on that, I developed an interest in seeing if we could apply this approach to treat allergies, particularly food allergies, because I thought there was a bit of an unmet need for reliable therapies in this patient population,” said Markusic.
The digestive system is constantly awash in foreign proteins in the form of food, and the immune system usually avoids attacking them (3). Markusic’s team wondered if expressing an allergenic food protein in the body would create immune tolerance for that protein that otherwise wouldn’t exist. They also specifically wanted to express that allergenic protein in the liver since the liver is home to cells that recognize native proteins and prevent the immune system from attacking them.
The researchers created mice with egg allergies by using “flaky tail mice,” a breed of mice with skin mutations that allow pathogens and allergens to more easily penetrate the body. Flaky tail mice can be made allergic to proteins by simply applying that protein, ovalbumin in this case, to their skin.
The researchers injected allergic mice with an advenovirus vector containing the gene for ovalbumin, which targeted the liver to induce tolerance. They then exposed the mice to environmental ovalbumin and measured their immune reactions.
Allergic mice that received the adenovirus treatment thrived compared to untreated mice, where the immune system went into overdrive, producing B cells, T cells, and a variety of antibodies in response to ovalbumin exposure. The average untreated mouse developed labored breathing, cyanosis around the mouth and tail, and hypothermia, symptoms of anaphylaxis. Treated mice showed barely detectable immune responses, maintained their body temperatures, and at most, experienced light itching and scratching.
Markusic and his coauthor Miguel Gonzalez-Visiedo hope that a one time or occasional injection treatment similar to what the mice received will be a better alternative to current food allergy treatments.
Suzanne Barshow, an allergist and immunologist at Stanford University who wasn’t involved with the research, was interested in the concept of gene therapy but isn’t ready to crown it as the next big thing. “That this gene therapy vector was able to prevent reactions is a good start. I think it's an interesting paper,” she said. But preventing an allergy from forming in the first place is likely simpler than eliminating an already existing allergy.
Whether being able to do that in mice will translate to humans is unclear. “We would definitely need more preclinical work to even discuss that further,” said Barshow. “At this point, we're really only identifying patients when it's known that they have an allergy already. Treating everyone before they go on to develop an allergy — that's not feasible.”
Barshow also pointed out that treating allergies with gene therapy may suffer from the same problems that vaccines have. “We don't know how long the effects of this injection would last,” she said. Protection could fade over time, potentially requiring repeated injections.
Markusic’s group next plans more preclinical work in dogs or nonhuman primates to sort out these questions.
- Gonzalez-Visiedo, M. et al. Single-dose AAV vector gene immunotherapy to treat food allergy. Mol Ther - Methods Clin Dev 26, 309–322 (2022).
- Jiménez-Saiz, R. et al. IgG1 + B-cell immunity predates IgE responses in epicutaneous sensitization to foods. Allergy 74, 165–175 (2019).
- Doherty, D. G. Immunity, tolerance and autoimmunity in the liver: A comprehensive review. J. Autoimmun 66, 60–75 (2016).
- Nowak-Węgrzyn, A. & Albin, S. Oral immunotherapy for food allergy: mechanisms and role in management. Clin Exp Allergy 45, 368–383 (2015).