Gene Therapy Helps Patients With Hemophilia B

Hemophilia is a rare inherited condition in which the blood doesn't clot normally. There are two main types, A and B. People with hemophilia B have a defect in the gene that makes clotting factor IX (FIX). As a result, these individuals are missing or have low levels of FIX, a protein produced by liver cells that is essential for normal blood clotting.

People with hemophilia B bleed more easily and severely after trauma than people without the disorder, and those with severe hemophilia may bleed with minimal provocation. Currently, treatment consists of routine infusions of FIX concentrates, in what is known as replacement therapy.

Because hemophilia stems from an abnormal gene, researchers have been exploring the potential of gene therapy to treat the condition, with the goal of correcting the defective gene by adding a normal gene. In new research funded in part by the National Heart, Lung, and Blood Institute (NHLBI), researchers showed that a single dose of an experimental gene therapy increased production of FIX in six people with hemophilia B. These promising results suggest that gene therapy may decrease or eliminate a patient's reliance on replacement therapy, thus providing a long-term solution for the prevention of bleeding episodes and, therefore, significantly improving a severely affected individual’s quality of life.

Overview of gene therapy

Genes are short pieces of DNA that provide the instructions for the body to make a specific protein or set of proteins. The Human Genome Project revealed that humans have about 20,500 genes. Genes help determine factors such as eye color and hair color, and they also can influence what diseases or conditions an individual may (or may not) get.

Gene therapy is an experimental technique that uses genes to treat or prevent disease. There are several approaches to gene therapy. These include:

• Correcting a missing or defective gene in a person’s cells by inserting a normal gene (this is the most common type of gene therapy).
• Repairing an abnormal gene.
• Altering the degree to which a gene is turned on or off.

Gene therapy is still in the experimental stage, and takes place only in clinical trials. The risks and limitations, as well as the benefits, are currently being assessed.

What was the study?

"Adenovirus-associated virus vector-mediated gene transfer in hemophilia B" was published in the New England Journal of Medicine online December 10 and in the print edition December 22, 2011.

• Six males, 18 years old or older, participated in the study. All had severe hemophilia B and were producing FIX at less than 1 percent of normal levels. The men were receiving standard replacement therapy consisting of regular infusions of manufactured FIX several times a month (2–3 times a week for five participants and once a week for one participant).
• For the gene therapy, the correct gene for FIX was inserted into a modified adeno-associated virus that targets liver cells (AAV8), used as the vector. Adeno-associated virus is a small, nonpathogenic single-stranded DNA virus from the parvovirus family. The AAV vector functioned as a carrier of the gene (genome), together known as the vector genome.
• Participants received a single injection into a peripheral vein of the AAV8 vector genome (vg) at one of three dose levels calculated on the basis of their weight. There were two participants at each dose level, and participants were monitored carefully before proceeding to a higher dose.
• Low dose: 2 × 10¹¹ vg per kilogram (kg) of body weight
• Intermediate dose: 6 × 10¹¹ vg per kg of body weight
• High dose: 2 × 10¹² vg per kg of body weight
• Participants were closely monitored following the vector infusion. Measurements included vital signs, plasma FIX activity (the amount of new FIX made by the inserted gene), and the participant’s immune response to the injected vg and new FIX.

What did the study find?

The experimental gene therapy technique boosted the production of the blood clotting factor FIX in all six participants with hemophilia B. After receiving the FIX gene therapy, each participant produced FIX at between 2 and 11 percent of normal levels (just 1 percent of normal can reduce bleeding events).

• In the short-term followup period (6–16 months), four participants no longer required FIX replacement therapy for routine bleeding, and two participants required FIX replacement therapy less frequently than before the study.
• Overall, there was a dose-response effect to the treatment. The participants who received the high level dose exhibited the highest levels of FIX expression (8–12 percent of normal).
• No immediate changes in vital signs were noted during or after the vector infusion in any of the participants.
• The effectiveness of the gene therapy appeared to be influenced by numerous factors, including the vg dose administered and the individual variation of immune response to the injected vg particles. No antibodies to FIX were detected in any participant.

What are the take-home messages?

• In this experimental treatment, a single injection of the AAV8 vg with the FIX gene allowed the six participants to make the necessary FIX protein at levels that were high enough to lessen their reliance on traditional replacement therapy. These findings show the potential for gene therapy to reduce the severity of the condition.
• While more research is needed, these results are more promising than prior attempts at gene therapy for the hemophilias.
• The long-term effectiveness and safety of this treatment will continue to be monitored.

Clinical trial participation

This study is currently recruiting participants with hemophilia B at three locations:

• Stanford Medical School, Stanford, California
• St. Jude Children's Research Hospital, Memphis, Tennessee
• Katharine Dormandy Haemophilia Centre and Haemostasis Unit, London, United Kingdom

For more detailed information on study participation, including eligibility requirements, please visit ClinicalTrials.gov.

Where can I learn more?

• Nathwani, A.C., Tuddenham, E.G.D., Rangarajan, S., … & Davidoff, A.M. (2011). Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. New England Journal of Medicine, 365(25), 2357–2365.
• Ponder, K.P. (2011). Merry Christmas for patients with hemophilia B. New England Journal of Medicine, 365(25), 2424–2425.
• Health Topic: What Is Hemophilia? (en Español)
• Gene therapy helps patients with hemophilia B; NIH-funded experimental treatment enhances body's ability to produce key clotting factor (News release)

Additional study information

• The work was led by researchers from the University College London Cancer Institute and St. Jude Children’s Research Hospital in Memphis, Tennessee.
• Organizations in the United Kingdom that provided funding for this research included the National Health Service, the National Institute for Health Research, the Department of Health, and the Royal Free Hospital. Funding sources in the United States included the Howard Hughes Medical Institute, the Assisi Foundation of Memphis, and the American Lebanese Syrian Associated Charities.

January 2012