Dr Frank Leebeek
Professor In Haematology, Erasmus University Medical Centre, Rotterdam
Dr John Pasi
Professor Of Haemostasis And Thrombosis, Bart’s And London School Of Medicine And Dentistry, London
After a 20-year seesaw of rising expectations and crushing failures, gene therapy is demonstrating its transformative potential in haemophilia A and B treatment.
Gene therapy has long been ‘the Holy Grail’ in haemophilia treatment, and after years of raised expectations and dashed hopes, the approach is finally starting to bear fruit.
Blood disorders are characterised by a lack of coagulation factor VIII in haemophilia A, or factor IX, in haemophilia B.
Replacing the burdensome regime of frequent prophylactic injections with a one-off treatment could be game changing for those living with these inherited blood conditions.
The most important thing is how it affects our patients, as individuals. If they are off prophylaxis and they are no longer bleeding, we have scored.
One-off treatment to replace multiple weekly injections
Professor in Haematology at Rotterdam’s Erasmus University Medical Centre, Dr Frank Leebeek, says: “We have treated six people, and between 100 and 200 have been treated worldwide.
“We are finding that after this single infusion, most people produce factor VIII or factor IX in their own liver.
“That prevents the spontaneous bleeds that can lead to arthropathy, and takes away the need for prophylaxis. They no longer need to infuse themselves two or three times a week and the haemophilia has essentially been cured.”
Professor Leebeek describes the treatment, which uses a recombinant adeno-associated virus (AAV) to deliver the missing DNA to the nuclei of liver cells, as “transformative”.
“For the patients we have treated, it has changed their lives completely. They no longer live in fear of having bleeds or needing another injection. They might be able even to undergo surgical procedures without coagulation concentrate.
“Some just can’t believe it. They no longer need prophylactic injections three times a week, or 150 times a year – that’s a huge improvement in quality of life,” he said.
Developing gene therapy has been complex – until 2011
It’s been a long road, explains Dr John Pasi, Professor of Haemostasis and Thrombosis at Bart’s and London School of Medicine and Dentistry.
“Gene therapy is often cited as the Holy Grail in haemophilia,” he says, explaining the aim of both traditional intravenous and newer subcutaneous prophylaxis treatments was to increase coagulation factor levels from less than 1% of normal to more than 1%.
“You don’t need much of an effect to change a person’s life; it’s easy to measure the effects of treatments through bleeding patterns, and haemophilia is caused by a single gene.
“That makes it an ideal target for gene therapy. But for 20-odd years, it was fraught with expectation and failure.”
All that changed in 2011, when a study from University College London’s St Jude’s showed it was possible to stimulate the expression of low levels of factor IX in haemophilia B.
An “explosion” of work followed, culminating in 2017, when researchers using “super active” versions of the factor IX gene recorded close to normal levels, up to 30%, in treated haemophilia B patients.
“The results changed the boundaries of the possible,” says Professor Pasi.
“Things have come a long way in the last five years. We used to talk about only needing 1% or 2%, but now we have seen all these hugely positive results, we have moved the goalposts,” he said.
“Without a shadow of a doubt, this could be game changing.”
Unanswered questions remain
It is still early days though, and, despite the positive results, many unanswered questions remain.
Researchers are unsure how long the results will last, if AVV antibodies will hinder the success of any repeat treatment if required, or what drives the wide variations in individual responses seen in the literature.
While few adverse events have been seen in the studies, which now cover a decade of procedures, some people have developed an increase of liver function tests.
Much more long-term follow-up data is needed before firm conclusions can be drawn, warned both professors.
“The studies have been incredibly positive. We’ve seen nothing that worries us in terms of safety, but we must make sure we’re aware of all the issues.
“The worst thing we can do is to tell people we have the Holy Grail, and then it doesn’t deliver,” said Prof Pasi.
“The most important thing is how it affects our patients, as individuals. If they are off prophylaxis and they are no longer bleeding, we have scored for our patients.”
