Gene therapy holds out prospect of haemophilia cure

Medical practice
“Leap forward towards gene therapy cure for haemophilia A,” reports The Guardian.

“Leap forward towards gene therapy cure for haemophilia A,” reports The Guardian.

"Leap forward towards gene therapy cure for haemophilia A," reports The Guardian.

A trial of a new genetic therapy carried out on 9 men with severe haemophilia – a bleeding disorder – showed encouraging results.

Haemophilia A is caused by a faulty gene that results in the liver not making make enough of the protein factor VIII, which allows blood to clot.

Another type, haemophilia B, has been successfully treated with genetic therapy, but until now that's not been possible for the more common haemophilia A.

The condition almost always develops in men. Those with severe haemophilia A must inject themselves every few days with factor VIII to prevent bleeding in the joints and soft tissue, which can be painful and damage joints. They're also at higher risk of bleeding in the brain, which can be fatal.

The technique used in this study made use of the little-known adeno-associated virus. This is a promising avenue for gene therapy, as modified forms of the virus can be used to deliver missing sections of DNA, but the virus itself doesn't cause any symptoms.

In this study, the virus was used to transfer the missing DNA to the liver cells so they can could start making factor VIII. This was done by a single injection.

Seven men who received a high dose of the therapy saw a big drop in the number of times they had bleeding episodes and could stop injecting themselves with factor VIII.

Bigger trials are now needed to ensure the therapy is safe for wider use and to look at the long-term effects.

Where did the story come from?

The trial was carried out by researchers from Hampshire Hospitals, University Hospitals Birmingham, Cambridge University Hospital, Addenbrooke's Hospital, St Thomas' Hospital, Imperial College London, and Barts and the London School of Medicine, all in the UK, and from BioMarin Pharmaceutical in the US, which is developing the gene therapy. BioMarin funded and designed the study.

It was published in the peer-reviewed New England Journal of Medicine on an open-access basis, so it's free to read online.

The Guardian and BBC News reported that 13 people have been given the therapy, although only 9 of them are included in the published study. The reports seem to be accurate and balanced.

What kind of research was this?

This was a dose escalation study, where people are given sequentially increased doses of a treatment to be sure it's safe before the next patient is given a higher dose.

These studies are a good way to find out what dose has an effect without causing immediate safety problems. But they're small and have no control group, so we can't use them to find out how well a treatment works compared with existing treatment.

What did the research involve?

Researchers recruited 9 men with haemophilia A to receive single injections of gene transfer therapy consisting of a modified version of the adeno-associated virus AAV serotype 5. The virus had been modified to carry the factor VIII-producing gene.

The men all had their regular factor VIII injections suspended for the trial, although they could use factor VIII if they experienced bleeding.

The first person was given a low dose, and the second person an intermediate dose. The third was given a higher dose, and when that was shown to work and not cause him problems, another 6 men were also given the higher dose.

All the men were monitored for a year.

Researchers checked:

  • levels of factor VIII (more than 5 international units [IU] per decilitre of blood was considered a success, and more than 50 IU is a normal level)
  • bleeding episodes
  • use of injected factor VIII
  • liver enzymes

There was no control group for comparisons, which would have used usual therapy such as regular factor VIII injections.

The researchers presented the results descriptively, giving information about what happened to each man in the trial.

What were the basic results?

The 2 men who had low or intermediate doses of gene therapy saw little change in levels of factor VIII, had continued bleeding episodes, and needed to continue injecting factor VIII.

Among the 7 men who'd had the higher dose:

  • all had levels of factor VIII of more than 5 IU per decilitre by 9 weeks after gene therapy
  • 6 had levels that reached a normal value (more than 50 IU per decilitre), and remained at that level a year after gene therapy
  • the average number of bleeding events fell from 16 before therapy to 1 after therapy
  • none of them developed antibodies against the factor VIII
  • all of them were able to stop injecting factor VIII

The men who had high-dose therapy all had an increase in a liver enzyme up to 1.5 times the normal level. But they didn't report having any symptoms from this increase, and liver cells continued to produce factor VIII.

How did the researchers interpret the results?

The researchers said they had carried out "successful gene transfer" and "the frequency of participant-treated bleeding episodes decreased markedly".

They added that a successful single-dose gene therapy for haemophilia A would lead to many benefits for patients "likely to provide increased quality of life".


This is a promising early trial of a therapy with the potential to make a great deal of difference to the lives of some people with haemophilia A.

But it's an early trial and there's still a way to go before the treatment can be considered a cure or used widely.

We need to see the results repeated in much larger groups of people to see what proportion of people with haemophilia benefit from gene therapy.

One problem is that gene therapy using this method is unlikely to work in people with antibodies against the carrier virus or clotting factors. This, says an expert in an accompanying editorial, means that "most people with haemophilia cannot yet benefit from gene therapy".

We also need long-term safety data in large groups of people to be sure the treatment doesn't cause serious health problems for some patients in the longer term.

The study was very small and didn't have a control group, so we don't know whether some people might have experienced the same outcomes in terms of bleeding events by continuing with regular factor VIII injections.

While needing only 1 injection of gene therapy is obviously more attractive than needing injections of factor VIII every few days, we don't yet know the cost of the new therapy.

If it's very expensive, researchers would need to show it had much better outcomes for patients before it would be used instead of the standard factor VIII therapy.

This isn't a cure for haemophilia, but it's a good step along the road to finding a cure.

Article Metadata Date Published: Thu, 14 Dec 2017
Author: Zana Technologies GmbH
NHS Choices