Hemophilia and Gene Therapy Treatments

“Puberty for me went off like a bomb. I started my period when I was 11 years old. The periods would last for weeks and weeks and I’d eventually be hospitalized each month. Eventually I developed ovarian cysts, which ruptured and bled in my abdomen. I was in excruciating pain,” Radford told Healthline.
Radford is one of the 20,000 people in the United States living with hemophilia, a genetic bleeding disorder that prevents blood from clotting normally.
For many with hemophilia, daily life consists of trying to avoid cuts and bruises. There are treatments but many are expensive and not effective for everybody.
However, new research is providing hope for people with this potentially dangerous disease.
Advances in gene therapy are showing enough promise that some experts say one day hemophilia may no longer be a lifelong ailment.
Hemophilia is more common in males, but females can also be affected by the disorder.
Girls and young women can experience heavy menstrual bleeding lasting more than seven days as well as hemorrhaging after childbirth.
Radford received a diagnosis at 7 months old when a small contusion on her head turned into a large bump.
She spent nine months in the hospital while doctors attempted to reach a diagnosis. Hospitalization was to become a recurring theme for Radford.
When she began menstruating, she was hospitalized for an extended period of time.
“I was airlifted to the children’s hospital in St. Johns Newfoundland and spent a year there. I turned 13 in the hospital while doctors pumped me full of blood and pain meds to try and stop the bleeding. Eventually a high-dose birth control worked and I’ve been able to manage my periods like that,” she said.
Hemophilia is caused by a decrease in one of the blood clotting factors, either factor VIII or factor IX.
The disorder can cause uncontrolled and spontaneous bleeding without an obvious injury. The level of bleeding risk is dependent on the level of clotting factor decrease.
Bleeds can occur both externally from cuts or trauma as well as internally in the spaces around the joints and muscles. If left untreated, the bleeding can cause permanent damage.
There’s currently no cure for hemophilia, but patients can be treated with an intravenous clotting factor.
“In hemophilia, patients are missing a single clotting factor protein, either factor VIII or IX, which arrests the progress of the clot formation putting patients at risk for serious bleeding, particularly recurrent bleeding into joints with subsequent development of crippling arthritis,” Dr. Steven Pipe, chair of the Medical and Scientific Advisory Committee of the National Hemophilia Foundation, told Healthline.
“To prevent this pathology, they administer ‘replacement therapy’ by infusing the factor VIII or IX proteins on a regular basis – typically every other day for factor VIII and 2 to 3 times per week for factor IX,” Pipe said.
Replacement therapies have revolutionized outcomes for those with hemophilia, but the treatment is not without its problems.
“When patients born with no expression of factor VIII or IX at birth are exposed to replacement proteins of factor VIII or IX, their immune system can mount a response to what it perceives as a foreign protein,” Pipe said. “These antibodies can inactivate the protein such that it will no longer treat or prevent their bleeding. This happens in up to 30 percent or more of patients with severe hemophilia A (factor VIII deficiency). These inhibitors require alternative but less effective treatments and lead to poorer outcomes for patients.”
In most individuals with hemophilia, regular treatment from infusions can prevent the vast majority of bleeding. But it comes at a heavy cost for both patients and caregivers.
Treatment for infants can begin at 1 year of age or earlier. Parents must learn how to administer treatments that can be as frequent as every second day.
“This comes at a tremendous cost to patients, families, and health systems. We know that joint disease can still appear in young adults and annualized bleeding rates are still not zero. There’s still room for new interventions that could improve patient outcomes even further,” Pipe said.
One of the interventions for hemophilia currently being explored is gene therapy.
This works by providing patients with hemophilia a new “working copy” of the genes for either factor VIII or factor IX.
The goal is to put the genes into cells in the body that are capable of making proteins. The most suitable organ for this is the liver.
“At present, all of the hemophilia gene therapy trials are using a virus called AAV (adeno-associated virus) to get the gene into the body,” Dr. Jonathan Ducore, director of the Hemophilia Treatment Center at the University of California Davis told Healthline.
“The AAV types used are ones which go to the liver and insert the gene (either factor VIII or factor IX) into liver cells. The viruses don’t divide and, so far, haven’t made people sick. Most researchers don’t believe that the virus will interfere with the normal liver genes and feel that the risk of causing severe liver damage or cancer is very low,” Ducore said.
With the genes enabling the person’s own liver to make the necessary proteins, plasma increases to a level that’s stable enough to eliminate bleeding risk.
Although there are still multiple trials taking place around the world, results have been life-changing for some of the participants.
“Subjects from the earlier trials who had good responses have successfully come off prophylactic factor replacement therapy, and have had dramatic reductions in bleeding, many with complete cessation of bleeding,” said Pipe, who is a lead investigator of a clinical trial conducted by the biotech company BioMarin. “Some of these clinical trial participants are approaching 10 years out from their treatment and still showing persistent expression. In several recent trials, the clotting factor levels achieved in many of the subjects have been within the normal range for factor VIII and IX,” Pipe said.
“This gives promise for a durable — if not lifelong — correction of the hemophilia. The biggest promise from gene therapy is to liberate patients from the burden and cost of prophylactic therapy,” Pipe added.
In studies with dogs, the clotting factor has successfully been produced for decades, but human trials haven’t been conducted enough to know how long the factor can be produced.
Researchers don’t yet know whether young people can be treated with gene therapy as current trials require all patients to be 18 years or older.
“There are questions about administering these viruses to younger children with growing livers. We don’t know if the liver is the best organ to target for the gene therapy. Factor IX is normally made in the liver, but factor VIII isn’t. We know that people will have immune reactions to the virus and that this can cause mild liver reactions and decrease the amount of factor produced. We don’t know the best way to treat this,” Ducore said.
Grant Hiura, 27, was diagnosed with severe hemophilia A at birth.
He self-infuses every second day. Despite the promising results of gene therapy trials, he’s apprehensive about the potential consequences on the blood disorders community.
“Whenever gene therapy comes up in the world of hemophilia, I always get cautious because that discussion inevitably ends in this very question of ‘ridding’ people of hemophilia,” Hiura told Healthline. “Given how tight knit the bleeding disorders community is, I think there’s a much bigger discussion that needs to be had about how this potential transition from being ‘born with hemophilia’ to being ‘genetically cured of hemophilia’ would play out within the community.”
“What happens if only a select portion of the community is able to access gene therapy?” he added. “How would we view those who have received gene therapy versus those who haven’t?”
Gene therapy, if successful, would provide a clinical cure, but not alter the genetic defect itself. As such, the reproductive inheritance of hemophilia in subsequent generations wouldn’t change.
Ducore says we’ll know more about how effective current gene therapies are for hemophilia in the next five or more years. We should also know whether they can create a better lifelong solution for those living with the disorder.
“Those patients volunteering for these trials are, in many ways, pioneers,” he said. “They’re exploring parts unknown, risking hardships — only some of which are known and only partially understood — in search of a better life, free from frequent injections and restrictions on their activities. We’re learning a lot from these pioneers and believe that the future will be better because of them.”