Hemophilia: Groundbreaking Gene Therapy Drug May Cure Dangerous Blood Disease

blood transfusion
An Indian medical assistant prepares a donor for the transfusion process at a blood transfusion clinic in New Delhi on June 1, 2016. CHANDAN KHANNA/AFP/Getty Images

Scientists announced last week that hemophilia might be curable with gene therapy. This week, they've announced that cure may become more accessible. The group behind a British clinical trial said Thursday that their gene therapy will be going global in the next stage of its development and plans for a phase III trial will include patients on four different continents—including some in the United States.

The results of the previous phase of the trial, published in the New England Journal of Medicine on December 9 and funded by biotechnology firm BioMarin, are astonishing. People with hemophilia had far, far fewer bleeding issues after receiving the gene therapy. Many people were able to sharply reduce the amount of artificial clotting factor they were taking, too. Some patients even saw the levels of clotting factors in their blood exceed those found in unaffected people for a while.

Bleeding doesn't sound all that bad. After all, that's what bruises are: just a bit of bleeding under the skin. However, unlike most people, hemophiliacs will bleed spontaneously and lack a protein that helps their blood clot. If bleeding happens in a person's joints, it can be very painful. If it happens enough, the damage can be debilitating. If it happens in a person's brain, their lives could be at risk.

Artificially adding even a little bit of the clotting factor that's missing can help; that's the standard treatment for severe hemophilia. According to Dr. John Pasi, director of the hemophilia center at Barts Health NHS Trust and a professor at Queen Mary University of London, keeping a baseline level of even 1 percent can be helpful. However, a lifetime of treatment can be pricey. In Britain, hemophilia can cost the equivalent of $135,000 per person per year.

blood bag
Blood is collected from a donor into a bag during a blood drive June 20, 2017 on Capitol Hill in Washington, DC. Treatment for hemophilia used to rely on plasma-derived clotting factors; now, most clotting factors are synthetic due to concerns about blood-borne illnesses like HIV. Alex Wong/Getty Images

Only about one in every 5,000 male children born have hemophilia, according to the Centers for Disease Control and Prevention. Girls almost never do; the disease is passed down, generally speaking, from mothers to sons. The genes that produce proteins that are vital to making blood clots are found on the X chromosome. Each person has two sex chromosomes; men have one X and one Y, while women have two copies of X chromosomes. Even if one copy of the gene is mutated, they've got a backup on the other X chromosome. Men, however, only have one version.

Like all gene therapies, these treatments work by compensating for that mutated gene. Scientists can piggyback off the body's normal processes to make cells produce something based on a normal version of a gene. The normal copy of the gene is carried into the body within a virus called an adeno-associated virus (AAV). These viruses, unlike viruses like the flu or HIV, can't cause disease in humans.

Hemophilia is perhaps best known because of its remarkable prevalence in Europe's royal families. Queen Victoria is thought to have been a carrier of a mutation that caused hemophilia B. The difference between the types of hemophilia can be found in which gene has been mutated and thus which clotting factor is affected. People with hemophilia A don't have enough clotting factor VIII; hemophilia B is linked to a mutation in clotting factor IX. Hemophilia A is about six times more common than hemophilia B.

"Hemophilia is a great disease target for gene therapy," said Pasi. "The cause and effect relationship is clear," he said, and that cause is just one gene. "It being a single gene disorder, you can replace that one gene and see the benefits."

Those benefits, in this case, were extraordinary. "If you've got severe hemophilia, to convert that into mild or moderate hemophilia you don't need much factor VIII expressed," Pasi said. Even just increasing the amount to about 5 percent of what would be seen in a normal person would make a huge difference; patients with those levels only need to be seen in a specialized clinic once a year.

At first, Pasi said, researchers expected that their gene therapy wouldn't quite get patients levels up that high. But they were proven wrong. Some patients had concentrations of clotting factors far above that 5 percent; in some, the concentrations were around what they'd be in a normal person. Two patients even had concentrations even higher than the normal range for a while. "We were just blown out of the water. It was amazing, it was something way more than we ever expected," Pasi said.

What the trial hasn't shown is if these levels will stick around for longer than a year—which is why Pasi is hesitant to really call what he and his team have done a cure. "We are really optimistic that it will last for a long time," he said. But similar work done with hemophilia B and in dogs give him reason for optimism.

In theory, a gene therapy treatment for hemophilia B was a bit easier to find. Viruses can only carry so much genetic material at a time; the genetic material needed to fix hemophilia A is about twice as large it is for hemophilia B, according to an editorial published in NEJM.

Though the results so far are promising, it's worth keeping in mind that the studies so far have been small and only done in adults with severe hemophilia. Whether this will work for children, for more mild forms, or in other centers is still an open question. But if those questions are answered, regulators in the U.S. and around the world could be evaluating a gene therapy for hemophilia A as soon as 2021.