The disease affects millions of people and is sometimes untreatable due to patients' immune systems rejecting the standard treatment--infusion with a protein that helps the blood to clot.
To help patients tolerate therapy, doctors try to exhaust patients' immune systems by administering the therapeutic protein intravenously at frequent intervals and for long periods until the body no longer responds by producing inhibitors. While that brute force approach works
for hemophilia A, it often doesn't for hemophilia B, in which patients risk death from anaphylactic shock if exposed to the protein therapy.
The authors of a paper in PNAS say they have devised a method that may help patients develop tolerance to the therapeutic protein before they are in need of treatment.
Researchers genetically modified plants to encapsulate a tolerance-inducing protein within cell walls so that when ingested, it can travel unscathed through the stomach and be released into the small intestines where the immune system can act on it. They then inserted the gene responsible for producing the protein into the genome of plants. To maximize the amount of protein produced, they inserted thousands of copies of the genes into chloroplasts — the energy-producing centers of plants — using a gene gun.
The encapsulated protein was fed to hemophilic mice for an extended period. Surrounded by the hardy plant cell walls, the protein was protected from digestive acids and enzymes while traveling through the stomach. Once it arrived safely in the small intestines, however, surrounding bacteria chewed on the cell walls, causing the protein to be released and acted on by the immune system to induce tolerance.
When the mice were later treated intravenously with the clotting factor therapy, they produced little or no inhibitors, and none developed anaphylactic shock.
Not only did the pretreated mice survive the once-deadly treatment — they also had a greater positive effect from therapy than did other mice.
"You may wonder, 'why hasn't this happened before,'" said Thierry Vandendriessche, Ph.D., an associate professor of medicine at the University of Leuven in Belgium. "It's because it was difficult to administer a high amount of protein in the right place and at the right time. I think this is a milestone — nobody has previously achieved such levels of robust immune tolerance by any means using a noninvasive procedure."
The researchers say they will continue to study how their method works, extend the approach to treating hemophilia A in mice and, ultimately, conduct trials in humans. Protein used in the human trials will be produced in lettuce and formulated to allow delivery of standard doses.
"We're hoping that our research will, in the future, result in better and more cost-effective therapies," said Roland Herzog, Ph.D., an associate professor of pediatrics, molecular genetics and microbiology in the UF College of Medicine and a member of the UF Genetics Institute, who was one of the study's leaders.
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