Gene therapy


Suzanne O'Callaghan is HFA Policy Research and Education Manager

For a long time gene therapy has been hailed as a potential ‘cure’ for haemophilia, but the expectation has been that viable treatment is many years away in the future. In December 2017 two international experimental gene therapy studies published successful results, creating a great deal of publicity and excitement that a cure for haemophilia might finally be within reach.


Gene therapy press conference
Mark Lee and family, Prof John Rasko and Daniel Credazzi at the haemophilia B study press conference


Dr Glenn Pierce, Medical Member of the World Federation of Hemophilia Board of Directors, spoke with HFA about the background to these current gene therapy studies and what it means for people with haemophilia.

HFA: What is gene therapy?

Glenn Pierce: Gene therapy means a drug therapy that delivers a gene, made of DNA, to treat a disease, instead of a protein or small molecule. In the past, proteins such as factor VIII and factor IX, have been used to treat haemophilia. In work over the last 30 years, scientists have investigated using the DNA for factor VIII or factor IX to treat haemophilia in animals and humans. 

HFA: How does gene therapy work?

Glenn Pierce: DNA can’t be delivered orally, and when delivered intravenously, needs to be protected or it will be destroyed in the bloodstream. Viruses have evolved over hundreds of millions of years to deliver their genes into our cells. They are very efficient, which is why so many viruses cause so many infections in us. Scientists have harnessed several viruses and removed their genes to insert the factor VIII or factor IX genes. One virus in particular, adeno-associated virus (AAV), has proved to be very effective in delivering new genes to animals and humans. Thousands of mice have been cured of their haemophilia, and several trials are underway in humans. 

HFA: What will the outcomes be for people with haemophilia?

Glenn Pierce: Early clinical trials in haemophilia were not successful but addressed many technical problems that needed to be overcome. More recent clinical trials using AAV-Factor IX have produced factor IX levels averaging 30% in persons with haemophilia B for at least one year. Likewise, a different biotech company has used AAV-factor VIII to produce on average 100% factor VIII circulating levels for at least one year. Many questions remain, including how long it will last and to monitor for long term safety.
HFA: What are some examples of gene therapy trials internationally now?

Glenn Pierce: Three companies are in advanced clinical trials and can be followed for clinical progress: Spark Therapeutics, BioMarin, and UniQure. 

Dr Glenn Pierce, MD PhD, is Medical Member, USA, of the World Federation of Hemophilia Board of Directors and is on the Medical and Scientific Advisory Council of the National Hemophilia Foundation (NHF), the medical body which makes policy for the American bleeding disorders community.


Media stories about the two gene therapy trials spoke of them as “a breakthrough” and “a giant leap forward” in the search for a cure for haemophilia. But what is meant by a ‘cure’ for haemophilia? 
In gene therapy this varies between studies. Around the world there are a number of gene therapy studies at different stages of development, and each study has its own measurements of success. The two gene therapy studies that published results in December are some of the most advanced: one trial in the UK studying haemophilia A and the other in the USA, Canada and Australia studying haemophilia B. Both of these studies were able to demonstrate that:
  • For most, factor levels could be increased and sustained at the mild haemophilia range or higher for at least one year
  • Prophylaxis treatment could be discontinued for all participants
  • Nearly all participants had no further bleeding episodes. 1,2


The haemophilia A gene therapy study took place across multiple centres in the UK and was sponsored by BioMarin Pharmaceutical. 9 men with severe haemophilia received a single infusion of AAV5 to deliver an altered human factor VIII gene into their body. One received a low dose, one an intermediate dose and 7 received a high dose. They were followed for a year.
The 2 men who received low or intermediate doses had factor levels that remained at 3% or lower (moderate haemophilia). Of the 7 men who received high doses, 6 gradually increased to normal factor levels and had maintained this a year after treatment. Prior to the gene therapy treatment, all 7 had been on prophylaxis treatment. By 22 weeks after treatment, all 7 participants no longer needed to use factor VIII treatment.1   
‘When we started out, we thought it would be a huge achievement to show a 5 per cent improvement, so to actually be seeing normal or near-normal factor levels with dramatic reduction in bleeding is quite simply amazing,’ said Prof. K. John Pasi, Director of the Haemophilia Centre at Barts Health NHS Trust and one of the trial investigators.3


The haemophilia B gene therapy trial was a collaboration between the team led by Prof. John Rasko at the Royal Prince Alfred Hospital in Sydney and multiple centres in the USA and Canada, and was sponsored by Spark Therapeutics.
In the study 10 men with haemophilia B and factor levels below 2% were treated with a single infusion of AAV with an altered factor IX gene. After treatment all had a substantial increase in their clotting factor IX (9) levels, which were sustained at a mean of approximately 30%, ranging from 14% (mild haemophilia) to 81% (normal range). As a result of this treatment nearly all had no further bleeding episodes. 8 out of 10 have not used clotting factor replacement therapy since then. Only one participant needed to use factor replacement therapy for bleeds after treatment, but used 91% less factor than before. There were no serious side effects.2 
Although this was a small study and has not yet had long-term follow-up, Professor Rasko sees this as a major step in haemophilia treatment. ‘We now know how to beat the immune response to achieve what may be a permanent cure,’ he said.
Professor Rasko explained that the success of this small clinical trial can now pave the way for a larger study in haemophilia B with long-term monitoring. His team at RPA and their collaborators in the USA and Canada will also be commencing a similar small experimental clinical trial in haemophilia A in 2018.



Before receiving the experimental gene therapy treatment, Australian clinical trial participant Mark Lee, 38, had severe haemophilia and clotting factor infusions up to three times a week since birth. Since the gene therapy injection his factor levels are in the normal range and he has not had any bleeds.
‘This is life-changing for me. I spent my childhood wrapped up in cotton wool, unable to play football or do any of the things my mates could. I would always remind myself that there were people worse off than me, but it was still disappointing,” said Mark Lee. “I have two daughters who are carriers for haemophilia, but now I know that if they have affected children, it could be one injection and they could live normal lives. This goes beyond our little family currently. It will have a positive impact on all generations to come.’
Mark commented that it is sometimes the little things that show how much difference this has made to his quality of life. He travelled by plane to the Sydney press conference to present the results. ‘I always used to wait for other people to get off the plane,’ he said, ‘but this time, I stood up, gave my knee a little wriggle and walked straight off with all the other passengers.’



There is still a long way to travel with both of these gene therapy trials. Both studies were very small – just 9 to 10 people with haemophilia – and before these treatments can be made widely available, there will need to be studies of much larger groups of people with haemophilia who, along with these participants, will need to be monitored for at least 15 years to confirm the results and check for other complications. 
Inclusion criteria were also very strict and limited the number of people who could participate and use the treatment. Both studies used an adeno-associated virus (AAV) to transport the corrected gene to the participant’s liver. AAV is a small virus that is not currently known to cause disease, but many people with haemophilia may already have been exposed to AAV and their immune systems could reject it. To take part in these trials, participants needed to be AAV negative. There are a number of gene therapy studies around the world using variations on AAV to deliver the gene within the body. All these studies have similar exclusion criteria, including other requirements; for example, participants also have to be adult males with severe or moderate haemophilia, without active hepatitis and have no history of inhibitors.4,5 A next step for the haemophilia A AAV5 study is to trial a high dose in a small number of people who are AAV positive to see what the outcome is.6


Apart from AAV, other types of gene therapy are also being studied, some with very promising results. Researchers are working on a range of methods to deliver the corrected gene within the body: lentiviruses have been used successfully in dogs with haemophilia; platelets derived from hematopoietic stem cells (which produce blood cells) are also being investigated to transport the corrected gene directly into the blood stream. Other forms of gene technology are also being researched, including gene editing and other novel approaches.5
Daniel Credazzi, Vice-President of Haemophilia Foundation Australia, who has a son with haemophilia, welcomed the breakthroughs, saying: ‘The real potential of a cure with safe and effective gene therapy is very exciting for people living with this chronic condition, and for their families. My wife and I have been looking forward to this news since our son was diagnosed with haemophilia 13 years ago. We are grateful to all the courageous people who have participated in gene therapy trials.’


For people with haemophilia in Australia, these are exciting times, with a range of new ground-breaking haemophilia treatments coming on to the market as well as the first indications of success in these experimental gene therapy trials. If you have questions about experimental gene therapy or other new haemophilia treatments, talk to your specialist haemophilia doctor (haematologist).
1. Rangarajan, S, Walsh, L, Lester, W. AAV5–factor VIII gene transfer in severe hemophilia A. N Engl J Med 2017;377:2519-2530
2.George, LA, Sullivan, SK, Giermasz, A et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017;377(23):2215-2227.
3.Paddock, C. Hemophilia cure? Gene therapy trial shows dramatic results. Medical News Today 15 December 2017 <>
4. Van den Berg, M. A cure for hemophilia within reach. N Engl J Med 2017;377:2592-2593.
5.George, LA. Hemophilia gene therapy comes of age. Blood Advances 2017;1(26)2591-2599.
6. BioMarin Provides 1.5 years of Clinical Data for Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A at 59th American Society of Hematology (ASH) Annual Meeting Concurrent with NEJM Publication. 9 December 2017 <>


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