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Hemophilia Genotyping Effort Funded by Biogen Idec Expanded Nationwide

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Originally published Oct. 8

After the successful deployment of a pilot genotyping project initiated at 11 hemophilia treatment centers last year, Biogen Idec and several research partners have decided to expand the program nationally to provide free genetic testing to hemophilia patients and store their blood samples, as well as genotype and phenotype data in a research repository.

Last year, Biogen Idec, the National Hemophilia Foundation, the American Thrombosis and Hemostasis Network, and Puget Sound Blood Center partnered to provide free genetic testing at a limited number of hemophilia treatment centers and build a research repository for storing their de-identified data, which researchers could apply to gain access to (PGx Reporter 11/14/2012). More than 270 people with hemophilia A and B were genotyped through this initial phase, and 90 percent have agreed to have their data and samples stored for research.

The collaborators now plan to roll out this project at 140 hemophilia centers with the goal of ultimately storing the samples and genetic information of 5,000 patients. Biogen Idec and its partners are hoping that this large repository will help researchers identify novel mutations and one day advance personalized treatment strategies.

Hemophilia is a bleeding disorder that occurs in patients with mutations in either the F8 or F9 genes that lead to a deficiency of the blood-clotting proteins Factor VIII and Factor IX, respectively. Changes in the F8 gene are responsible for hemophilia A, while mutations in the F9 gene cause hemophilia B.

Hemophilia A and B are rare, occurring mostly in men. Around 1 in 5,000 males are born with hemophilia A, and 1 in 25,000 men are born with hemophilia B. While most hemophilia-causing gene mutations are inherited, 30 percent of patients have no family history of the condition. Females can be mutation carriers but rarely get the disease.

By gathering genotype-phenotype data on a large number of hemophilia patients, the project collaborators are hoping to increase the research community's collective understanding of the disease. For example, why do some patients with severe hemophilia develop antibodies to the clotting factor concentrate they're treated with and which mutations are responsible for the variability in bleeding severity seen among hemophilia patients?

Biogen Idec is providing the financial support for the program, called "My Life, Our Future: Genotyping for Progress in Hemophilia," and is helping to develop the genotype-phenotype database. The company hasn't provided a cost estimate for the pilot or the national roll out.

Genetic testing for hemophilia patients can cost between $500 and $3,000 depending on the technology used and the lab performing the analysis. While the genotyping is free for hemophilia patients through the "My Life, Our Future" program, individual hemophilia centers can ask patients to pay for associated costs, such as the clinic visit, the blood draw, or consultations with healthcare providers.

The ATHN will set up a multidisciplinary research review committee, including scientists, consumers, and healthcare providers, which will review proposals submitted by researchers. Researchers with proposals the committee green lights will have access to the repository. "Qualified scientists, be they from industry or academia, can submit a proposal," Barbara Konkle, director of clinical and translational research at Puget Sound Blood Center, told PGx Reporter. Biogen Idec, Puget Sound Blood Center and other program coordinators will not have special access to the patient samples or data in the repository.

The project participants used the pilot project to refine the educational and consent protocols before expanding the effort nationally. The collaborators' experience launching a national genotyping program for a rare illness illustrates the complexities of such an undertaking. In particular, the research aspect – where patients and parents of young children are asked if they want to donate blood samples and have their DNA data linked with de-identified clinical data in a repository – made the consent procedures more complex.

"We found we needed to change our approach in explaining [the research repository]," Konkle acknowledged. "Our explanation was a little cumbersome."

Initially, the project organizers divided the research consent portion into different parts by how much blood patients would send in, whether they consented to give extra blood, and how they would consent to have their clinical data linked. "And it was just confusing," Konkle explained. "It wasn't so much that the patients didn't understand the research protocol, it was that the staff found it really complicated to explain the choices in the project."

For the national rollout, the consent process has been streamlined. Staff at hemophilia centers will present patients with two choices – they can either just get genotyped for free or they can also participate in the research repository. Then, if they chose to participate in the research portion they can choose how much blood to donate. "That may seem obvious now, but when you begin working on a complex research protocol, it doesn't always start being worded in the best way," Konkle said.

There is no funding in the project to compensate the staff at hemophilia centers for their time and effort explaining the genotyping and research program to patients. At the Puget Sound Blood Center, for example, all hemophilia patients are genotyped whether or not their insurance pays, which keeps the staff well occupied. Having to explain a research project is an added commitment. "The clinics are really busy and we're aware of that," Konkle observed. "So, we wanted to make it so this effort fit into their busy clinic schedules but still allow that the patients were given a good amount of time to understand the project."

The consent form for the research project has to be approved locally and each of the hemophilia centers participating in this program must gain clearance from their institutional review boards.

It is up to the patients and the parents of children as to how much blood they want to donate for research. The maximum amount of blood anyone can donate is 16 cc and the minimum is 2 cc. There is a lower blood draw range for very young children.

"The treatment for hemophilia is an intravenous infusion and the parents and patients learn how to do that themselves. So, being stuck and having blood drawn is not something that's unusual for these patients," Konkle said. "The fact that many of these patients will be donating additional blood samples is the reason we decided not to obtain DNA in other ways, like through buccal swabs."

When centers draw the blood, some of it needs to be processed immediately. "We're very flexible. We'll take what we can get for the repository," Konkle said. "If we don't have that much DNA, we will still put their Factor VIII or Factor IX sequence into the repository" if they want to participate.

The collaborators are hoping that the repository will have enough samples by 2015, so that it can be opened up to research applicants. With the help of the database researchers can explore the factors that influence patients' bleeding severity or investigate why some patients develop an immune response to treatment

However, in order for researchers to advance personalized treatment strategies for hemophilia, the database will have to collect many more samples. Once the database holds approximately 5,000 samples, "then we will definitely have the possibility for researchers to ask those questions," Konkle said.

Biogen Idec is footing the bill to test between 5,000 and 10,000 hemophilia patients and their families. The firm is currently committed to backing this effort for three years.

People with hemophilia A and B are treated by increasing the level of clotting factor in their blood through prophylaxis to prevent future bleeds or are given "on-demand fusions" to stop them from bleeding during an event. Biogen Idec is developing long-acting clotting factor replacement therapies and earlier this year filed for regulatory approval of Eloctate, a recombinant factor VIII Fc for hemophilia A, and for Alprolix, recombinant factor IX Fc for hemophilia B.

As researchers identify new mutations associated with hemophilia through this genotyping effort, the program coordinators plan to submit that information to open access databases housed at the Centers for Disease Control and Prevention so researchers worldwide can benefit from this knowledge. In the consent process, patients can give permission for researchers to share their data in such databases. "We know that's very important to do … So, we put that in [to the consent process] so we can contribute," Konkle said.

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