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Blizard Institute - Faculty of Medicine and Dentistry

Q&A: The efficacy and safety of using adeno-associated virus-mediated gene therapy to treat patients with Haemophilia A

Researchers led by Professor John Pasi from the Blizard Institute have demonstrated the efficacy and long-term safety of adeno-associated virus (AAV)-mediated gene therapy to treat Haemophilia A over three years. In this Q&A, Professor Pasi discusses why this study is important, and the wider implications for the research.

Digital graphic image of red blood cells


A lack of factor VIII causes Haemophilia A, which accounts for around 80 per cent of all Haemophilia cases. With the blood unable to clot, patients are at risk of excessive bleeding from even the slightest injury – as well as potentially life-threatening spontaneous internal bleeding. Patients have to undergo three or more intravenous injections each week to control and prevent bleeding. Eliminating these regular injections greatly reduces the burden of treatment needed to keep bleeding at bay.

Clinical researchers led by Professor John Pasi first announced in 2017 that 85 per cent of men treated with a single infusion of a missing gene were showing normal or near-normal levels of the blood-clotting protein, factor VIII, one year on.

In this new paper, Professor Pasi confirmed that all the patients involved in the trial were still benefiting from a substantial fall in the rates of bleeding three years after receiving the treatment. None of the 13 patients had required regular factor VIII to prevent bleeding during that period.


What is new about the study?

This is a two to three-year follow up of the previous study we published in 2017 – at two to three years out, participants had sustained clinically relevant benefit as measured by a substantial reduction in annualised rates of bleeding and complete cessation of prophylactic factor VIII use in all participants at both does used in the study.

Is there anything surprising about the results?

In one way no, but equally the fact we saw sustained expression is really important as is the fact that the treatment is safe.

Why is the study important?

Haemophilia is a severe bleeding disorder requiring treatment with intravenous injections every other day. Without injections, patients bleed into joints, develop disabling arthritis and are at risk of life-threatening bleeding. Replacement treatment is hugely demanding without guaranteeing protection against bleeding. Regular injection treatment starts before two years old so the accumulated treatment burden by adulthood is massive. For years, being a single gene disorder haemophilia has been seen as an ideal gene therapy target. The few previous gene therapy studies in haemophilia A pre-2017 were all singularly unsuccessful. Our study originally showed that it was possible to use gene therapy to express factor VIII in man at levels that were unexpected. The questions that arose from that initial observation were naturally about the further safety, durability and longer term effectiveness of this approach to gene therapy in man. This study with the long-term follow up confirms the safety and demonstrates durable efficacy. This data adds to the field and knowledge of these key questions in gene therapy. At the end of the day, the opportunity to provide a long-term treatment for haemophilia A, prevent bleeding effectively and stop regular intravenous injections has a huge potential globally to transform care and massively improve the quality of life for sufferers.

What are the wider implications?

Essentially this is a pioneer programme being the first in the field for haemophilia A (see above for some of the other issues). In addition, we report information that contributes to a growing understanding of AAV vector biology. 

More information

  • Research paper: ‘Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. K. John Pasi, M.B., Ch.B., Ph.D., Savita Rangarajan, M.B., B.S., Nina Mitchell, M.B., B.Chir., Will Lester, M.B., Ch.B., Ph.D., Emily Symington, M.B., B.S., Bella Madan, M.D., Michael Laffan, D.M., Chris B. Russell, Ph.D., Mingjin Li, M.Sc., Glenn F. Pierce, M.D., Ph.D., and Wing Y. Wong, M.D. New England Journal of Medicine. DOI: 10.1056/NEJMoa1908490.
  • Find out more about Barts and the London School of Medicine and Dentistry, Queen Mary University of London.

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