Gene therapy for bleeding disorder Hemophilia B

By Dr. Ananya Mandal, MDDec 12 2011

In a landmark study, researchers used gene therapy to successfully treat six patients with severe hemophilia, a blood-clotting disorder. Despite the early nature of the study, it is promising. A single infusion using the new treatment worked in some patients for more than a year, boosting their clotting ability significantly.

“I think this is a terrific advance for the field. It's a good lesson in terms of don't give up on good ideas,” said Dr. Ronald Crystal, chairman of genetic medicine at New York City's Weill Cornell Medical College, Dr. Katherine Ponder, a Washington University School of Medicine physician also called it a landmark study. She praised the research in an editorial that accompanies the study's publication in the New England Journal of Medicine. The research also was being presented Saturday at an American Society of Hematology conference in San Diego.

Hemophilia is an inherited, potentially life-threatening disorder affecting an estimated 20,000 Americans, almost all of them males. Their blood doesn't clot properly because of a faulty gene. People with hemophilia B have an error in their genetic code, which means they cannot produce a protein called factor IX, which is critical for blood-clotting. In severe cases, they can spontaneously start bleeding internally, even in the brain. Internal bleeding in the joints leads to debilitating movement problems and intense pain.

Since the late 1960s, doctors have given hemophiliacs infusions of clotting proteins. It's been a success, increasing their average lifespan to 63. But for severe cases, treatment can involve two or three infusions every week and cost more than $250,000 annually. Patients are currently treated with factor IX injections, sometimes multiple times per week, but the manufacturing process is also expensive.

There have been attempts to cure it in the past with gene therapy but the experiments improved blood-clotting for only a few weeks. “We couldn't make it last,” said Val Bias, chief executive of the National Hemophilia Foundation. Experts said the new method needs to be tested on many more patients to confirm it's effective and prove there are no risks. Even if all goes right, it's still several years away from being available to most patients.

The latest study was led by researchers at the University College London Cancer Institute and St. Jude Children's Research Hospital in Memphis, Tenn. All six of the patients in the study were men seen in London who had severe forms of type B hemophilia. The six men each got a single, 20-minute infusion of healthy genetic material delivered by a virus found in monkeys. Viruses are often used to transport DNA into cells.

The researchers took a virus which infects people without symptoms - adeno-associated virus eight. It was then modified to infect liver cells with the genetic material for factor IX. The gene should then persist in the liver cells, telling the cells to manufacture the protein.

Each saw the amount of clotting proteins in their blood increase from less than 1 percent of normal levels to at least 2 percent, and in one case as much as 11 percent. The rise was enough to allow all the men to ease back on the number of regular treatments they needed, and four stopped conventional treatment altogether.

In one patient, the level of liver enzymes shots up to five times normal levels. It did not cause symptoms but there are concerns about liver inflammation and he was treated with steroids. Researchers noted it's possible the treatment could trigger hepatitis in some patients.

Dr Amit Nathwani, the study leader, from University College London told the BBC that patients with 12% of normal factor IX production would no longer be seen in the clinic. “They would be able to go about their normal daily lives without any problems. The only time that they would have a problem is if they were involved in a road traffic accident or had a big fall from a building site. In the absence of severe major trauma these individuals would not know that they have hemophilia.” He said the aim of the research was to take patients from a severe form of hemophilia to a mild one.

“All the patients have actually benefited from this gene transfer approach, even the patients who have not been able to stop protein concentrate infusion [normal therapy].” He said these people needed fewer injections of factor IX. “This is the first study that has shown that you can actually achieve stable, long-term, therapeutic level of expression [factor IX production] in subjects with severe hemophilia B, so it's a fantastic start. This is a great breakthrough, this is the first time that anybody has been able to show that.”

Chris James, chief executive of the Hemophilia Society, said, “The society is delighted to see world-class research in the UK which may ultimately provide therapies to improve the life of those with hemophilia showing such positive results at this stage. These are early days and all medical and scientific developments need to go through extensive testing for efficacy and side effects. As such we would not wish to raise false hopes at this stage. However, we hope that this research will eventually result in the removal of the need for regular injections and significantly reduce painful bleeds and debilitating joint damage for those living with hemophilia.”