The standard treatment for haemophilia is infusion with an expensively produced protein that helps the blood to clot. But in some patients the immune system fights the therapy, and in a subset of those, it sets off an allergic reaction that can result in death.

Developing tolerance

Now researchers at the University of Florida and the University of Central Florida have devised a way that potentially could help patients develop tolerance to the therapeutic protein before they are in need of treatment.

They genetically modified plants to encapsulate the 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. The low-cost plant-based system, now being tested in mice, eventually could help improve the lives of many people who have haemophilia and dramatically reduce related health-care costs. The findings were published recently in the Proceedings of the National Academy of Sciences.

Haemophilia is characterized by defects in the gene that produces a protein required for blood to clot. People with haemophilia can suffer from spontaneous internal bleeding or severe bleeding resulting from minor injuries.

Males get the disease, which is linked to the X chromosome, while females are “carriers” who rarely exhibit symptoms. The two forms of the disease — haemophilia A and B — are associated with the absence of proteins called factor VIII and factor IX, respectively.

Haemophilia treatment consists of infusing the missing protein into a patient's blood. But in 25 per cent of patients, the immune system rejects the therapy and makes inhibitors that stop the clotting factor from taking effect.

In haemophilia B, up to 4 per cent of patients develop inhibitors to the protein therapy and many develop severe systemic allergic reactions, called anaphylaxis, which can be life-threatening.

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 haemophilia A, it often doesn't for haemophilia B.

New, gentler approach

To find a new, gentler approach to developing tolerance, one of the study's leaders, Roland Herzog, of University of Florida teamed with Henry Daniell, of the University of Central Florida, who has spent the last two decades developing transgenic plants for producing and delivering oral vaccines and immune-tolerant therapies.

They inserted the gene responsible for producing the therapeutic 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 centres of plants — using a gene gun.

The research team fed the encapsulated protein to haemophilic mice for an extended period. 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, according to a University of Florida press release.

When the mice were later treated intravenously with the clotting factor therapy, they produced little or no inhibitors, and none developed anaphylactic shock.