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Using Plant Cells to Help Treat Hemophilia

  • Synopsis: Published: 2014-09-05 - Researchers develop a way to use plant cells to teach the immune system to tolerate rather than attack blood clotting factors. For further information pertaining to this article contact: April Frawley Birdwell - Editor - College of Medicine Science Writer - University of Florida at Email: afrawley@ufl.edu Ph. 52-273-5817.

Hemophilia
Hemophilia (heem-o-FILL-ee-ah) is a disorder of the blood-clotting system. Hemophilia is a rare bleeding disorder in which the blood doesn't clot normally. If you have hemophilia, you may bleed for a longer time than others after an injury. You also may bleed inside your body (internally), especially in your knees, ankles, and elbows. This bleeding can damage your organs and tissues and may be life threatening. There are several types of hemophilia. All types can cause prolonged bleeding. Hemophilia usually is inherited, meaning that the disorder is passed from parents to children through genes.

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"The treatment would not be a one-time solution, however. Patients would need to continue taking the plant capsules to maintain immune system tolerance."

Accidents as minor as a slip of the knife while chopping onions can turn dangerous for patients with hemophilia, who lack the necessary proteins in their blood to stem the flow from a wound.

People with severe hemophilia typically receive regular injections of these proteins, called clotting factors, as a treatment for the disease. But up to 30 percent of people with the most common form, hemophilia A, develop antibodies that attack these lifesaving proteins, making it difficult to prevent or treat excessive bleeding.

Now, researchers from University of Florida Health and the University of Pennsylvania have developed a way to thwart production of these antibodies by using plant cells to teach the immune system to tolerate rather than attack the clotting factors. The study was published Sept. 4 in the journal Blood.

"The only current treatments against (antibody) formation cost $1 million and are risky for patients," said Henry Daniell, Ph.D., interim chairman of biochemistry at the University of Pennsylvania School of Dental Medicine and a co-author on the study. "Our technique, which uses plant-based capsules, has the potential to be a cost-effective and safe alternative."

The study focused on hemophilia A, which occurs when babies are born with a defective gene on the X chromosome. Because girls have two X chromosomes - giving them two shots at having a working version of the gene - the disease typically only affects boys. Worldwide, one in 7,500 male babies is born with this disease.

After receiving factor VIII treatments, between 20 and 30 percent of patients develop antibodies against the clotting protein. Instead of allowing the protein to do its job, the immune system responds to this foreign protein as an invader that must be attacked and eliminated.

"In the hemophilia world these antibodies are known as inhibitors," said UF co-author Roland Herzog, Ph.D., a professor of pediatrics in the UF College of Medicine and a member of the UF Genetics Institute. "That is what patients are all scared of, because they render their standard therapy ineffective and inhibit the blood from clotting."

Daniell and colleagues had developed a platform for delivering drugs and bio-therapeutics using genetically modified plants to express proteins. After teaming with Herzog and his colleagues at UF, they devised a way to use this technique to stop the body from launching an immune attack on the hemophilia treatment.

Using a combination of factor VIII DNA and another substance that can safely cross the intestinal walls and enter the bloodstream, the researchers fused the genes into tobacco plants. The team fed the resulting plant solution to mice with hemophilia A twice each week for two months and compared them with mice that were fed unmodified plant material. They then gave the mice infusions of factor VIII, just as human hemophilia patients would receive. As expected, the control group formed high levels of inhibitors. In contrast, the mice fed the experimental plant material formed fewer inhibitors - on average, seven times fewer.

"This could potentially be a way to prevent antibodies from forming or lower the incidence of it," Herzog said. "This is a major step forward."

The researchers discovered the mice that ate the experimental plants had more signaling molecules associated with suppressing or regulating immune responses, while mice in the control group had more associated with triggering an immune response.

The researchers also tested whether the plant capsules would help reduce antibodies in mice that had already developed them. After two to three months of feedings with the plant capsules, the mice had three to seven times fewer antibodies than before the treatment began.

"We have been looking for a way to induce immune tolerance in hemophilia for a while," Herzog said. "Oral tolerance is ideal is because you are feeding them something specific that addresses the problem and you don't have to use drugs that suppress the immune system. It's not invasive. You're not manipulating patients' cells. It would be an ideal way to do it."

The treatment would not be a one-time solution, however. Patients would need to continue taking the plant capsules to maintain immune system tolerance. When translated to humans, the researchers will use lettuce plants instead of tobacco plants.

Daniell, Herzog and the Penn Center for Innovation are now working with a pharmaceutical company to test this strategy in other animal species, with plans to begin human trials shortly thereafter. For human use, the goal would be to use lettuce plants instead of tobacco plants.

"With multi-million-dollar funding from a global pharmaceutical company and their decades of expertise in bringing numerous protein therapeutics to the clinic, we're excited to take lettuce capsules producing human blood clotting factors to the clinic soon," Daniell said.

The study was supported by the National Institutes of Health and Bayer. Other authors included Jin Su and Shina Lin from the University of Pennsylvania, and Alexandra Sherman and Xiaomei Wang at UF.



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