Genetics and stem cells

Gene therapy used to treat haemophilia

An experimental gene treatment means that people with haemophilia B may no longer need medication, BBC News has reported.

The news is based on a study that looked at using gene therapy to treat haemophilia B, a genetic condition that prevents the body from producing a functional version of a protein called factor IX (FIX), which is required for blood clotting. It is currently treated with frequent injections of FIX protein.

In this study, six people with severe haemophilia B were injected with a virus carrying a section of DNA that contained instructions for making the normal form of human FIX. All six had increased levels of FIX in their blood after treatment, and these levels continued throughout the follow-up period (up to 16 months). Four of the six participants were able to stop their regular injections of FIX protein, and the other two required fewer injections than before. The therapy also caused few side effects.

This exciting finding suggests that gene therapy for haemophilia B might be safe and effective. However, it will now need to be tested in larger numbers of patients who are followed for longer periods of time to fully understand the benefits and risks of this potentially powerful therapy.

Where did the story come from?

The study was carried out by researchers from University College London and other research institutes and hospitals in the UK and US. It was funded by the Medical Research Council, the National Institute of Heath Research and other organisations. The study was published in the peer-reviewed journal The New England Journal of Medicine.

This story was covered accurately by the BBC.

What kind of research was this?

This clinical trial tested gene therapy for treating the genetic disease haemophilia B, also known as Christmas disease. People with haemophilia B tend to bleed excessively if they have an injury, and sometimes have spontaneous internal bleeding without being injured. It is caused by defects in a gene on the X-chromosome, which contains the code for producing a protein called factor IX (FIX), required for blood clotting. The disease overwhelmingly affects males as the gene is located on the X-chromosome. Men only have one X chromosome, while women possess two and, therefore, are far more likely to have at least one working copy of the gene.

Currently, haemophilia B is treated with frequent injections of a concentrated form of the FIX protein. It is hoped that an experimental technique called gene therapy could offer a cure, as it could potentially be used to provide the body with a normal copy of the defective gene. In theory, this would allow the body to make its own FIX protein. Even if a little FIX protein is made, this would be helpful as an increase in FIX levels to just 1% of normal can substantially improve symptoms.

The current study was a combined phase I and phase II trial conducted as a case series, in which all participants received gene therapy. Phase I and II trials are usually small studies, primarily used to determine what dose of therapy is required and to assess its safety.

In this particular study, there was no comparison group who received a placebo or standard treatment. Generally, before a therapy can be approved by regulatory agencies, it needs to be shown to be effective in a phase III trial. Phase III trials are randomised controlled trials on larger groups of patients that include a control group, to test whether the new treatment is better than placebo or the current standard treatment.

What did the research involve?

The researchers modified a virus (called adenovirus-associated virus 8) so that it contained DNA that carried the instructions for making normal human FIX. Introducing DNA to a virus in this way means that it can be injected into a person and the virus will insert the DNA into cells. Once inside these cells, the DNA can be used by the cells’ machinery to produce a normal version of the FIX clotting protein.

Six men with haemophilia B and FIX activity level below 1% of normal were enrolled in the trial. They received a single dose of the modified virus injected into a vein. The virus targets liver cells and delivers the DNA there, allowing the liver cells make the FIX protein.

The participants were split into three groups and given a high, intermediate or low dose of the gene therapy. The patients were then followed for between 6 and 16 months, and tested to see how much FIX protein they produced, whether they could stop their FIX protein injections, and whether they showed any side effects.

What were the basic results?

The researchers found that after treatment with gene therapy, the participants showed increased FIX levels that were 2-11% of normal levels. These levels persisted through the follow-up period (up to 16 months). Four of the six participants could stop regularly injecting FIX protein concentrate without experiencing spontaneous bleeding, even when they participated in activities such as sport that had caused bleeding in the past. The other two participants were able to go for longer between FIX protein injections.

None of the participants developed an immune response to the FIX protein (their immune system did not mount an attack against it). There was an immune response against the virus used to introduce the DNA, but the timing and the strength of the immune response varied between participants. The two participants who received the highest dose of the DNA-containing virus had the strongest responses. In both participants, the immune response was successfully treated with steroids.

How did the researchers interpret the results?

The researchers concluded that a single dose of gene therapy resulted in FIX levels sufficient to improve the bleeding symptoms, with few side effects. They say that gene therapy could potentially give people with severe bleeding symptoms from haemophilia B “a mild form of the disease or … reverse it entirely.”


Patients with haemophilia B have defects in the gene normally used to produce the important blood-clotting protein FIX. Patients with severe haemophilia B have less than 1% of normal levels of functional FIX protein. The exciting finding of this study suggests that gene therapy might be a safe and effective way to increase the level of FIX in haemophilia B patients’ bodies, in some cases removing the need for FIX injections altogether.

In this study, prolonged production of functional FIX protein was observed after injection with a single dose of virus carrying a normal version of the FIX gene, and few side effects occurred. However, this was an early-stage, relatively short, small study with only six participants and no comparison group. As the researchers themselves concluded, follow-up of larger numbers of patients for longer periods of time is necessary to fully define the benefits and risks of this therapy, and to find the optimal dose.

NHS Attribution