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Could lettuce help save a life? IU researchers think so.


Eat your vegetables.

Research at Indiana University School of Medicine is putting a new spin on a familiar dinner table entreaty, offering hope to many patients with hemophilia.

Investigators in the Department of Pediatrics are working to help the 6,600 people in the United States—and others around the world—whose immune systems reject treatment for hemophilia. And one of their leading solutions may surprise you: lettuce.

But not just any lettuce. Roland Herzog, PhD, and his team in the Gene and Cell Therapy Program at the Herman B Wells Center for Pediatric Research are collaborating with investigators at the University of Pennsylvania to create a specially engineered version of the produce.

What is hemophilia?

Most people have proteins in their blood plasma that promote clotting when they start to bleed. These proteins, called clotting factors, are necessary to prevent prolonged bleeding. For people with hemophilia, whose blood contains less than 50 percent of one of the essential clotting factors, an excessive internal or external bleed can be life-threatening.

Roland Herzog, PhD

 The Centers for Disease Control estimates that there are approximately 20,000 people in the United States who have hemophilia, and about 400 babies are born with the rare condition each year.

While there is no cure for hemophilia, clotting factor replacement therapy is the most common treatment. It involves injecting a concentrate of one of the clotting factor proteins back into the body. Depending on the severity of the condition, replacement therapy may be necessary up to three times a week in order to be effective. Unfortunately, this treatment only works for two-thirds of patients.

What about the others?

For the other patients, the body develops antibodies that prevent replacement therapy from being effective. Alternative options are scarce, and these patients have to resort to difficult, invasive and costly choices that offer no guarantee of success. For these patients, even a minor bleed can pose a very serious threat.

That’s where investigators in the Gene and Cell Therapy program come in. In addition to developing ways to correct the disease entirely, a major focus in their program is to examine the interaction between gene therapies and the immune system that can help induce tolerance to replacement therapy. In a collaborative effort with investigators at the University of Pennsylvania, they’ve helped to create genetically engineered lettuce plants that could offer a noninvasive solution.

 So, could lettuce save a life?

In short—yes. The group has collaborated for more than a decade to define the mechanisms of oral tolerance and refine the biotechnology that allows the plants to deter inhibitor formation.

Henry Daniell, PhD, a professor of biochemistry at the University of Pennsylvania, and his laboratory provide the plant biotechnology, while Herzog’s team provides their expertise in hemophilia and immunology. Their goal is to engineer lettuce plants that effectively induce tolerance to clotting factor replacement therapy—and they’ve been quite successful.

“These lettuce plants are designed to express high levels of a clotting factor protein in chloroplasts,” Herzog said. “During photosynthesis, the chloroplasts in the plant’s green leaves fill up with either the clotting factor VIII or clotting factor IX protein. When the plants are ready to be harvested, the leaves are freeze dried and later ground into a powder, which is stable and effective for at least two years.”

So far, the group has seen success in animal models with both major forms of hemophilia. In 2015, the group successfully suppressed inhibitor formation in animal models with hemophilia B, which results in a lack of clotting factor IX. In a study published last year, they had success in models with hemophilia A, which is about four times more common than hemophilia B and results in a lack of clotting factor VIII. Importantly, hemophilia A also sees a higher proportion of people who develop the immune response that leads to treatment rejection.

Herzog said that he envisions a future where this powerful plant powder is orally delivered, perhaps in capsule form, to mature adults who suffer from immune rejection. Since the disease is genetic and impacts children early in life, it may be most effectively delivered in their food—such as baby food, juice or yogurt.

For now, the group continues to perfect the process and work their way toward clinical trials—which they foresee in the next 2-5 years.

Roland Herzog, PhD, is the Riley Children’s Foundation Professor of Immunology in the IU School of Medicine Department of Pediatrics. He is the director of the Gene and Cell Therapy Program in the Herman B Wells Center for Pediatric Research.

 Other IU investigators to contribute to this work include Naro Biswas, PhD; and Alexandra Sherman, DVM.

 This work is in collaboration with Henry Daniell, PhD, professor of biochemistry at the University of Pennsylvania. Projects referenced are largely funded by the National Heart, Lung and Blood Institute.

The views expressed in this content represent the perspective and opinions of the author and may or may not represent the position of Indiana University School of Medicine.

Sara Buckallew

Communications Coordinator

Sara Buckallew works in the Dean's Office of Strategic Communications. As a communications coordinator, Sara supports internal and external communication needs for the Herman B Wells Center for Pediatric Research and the Center for Diabetes and Metabolic...