Advancing gene therapy: a cure for haemophilia?

In the UK, haemophilia affects around 6000 people – mainly boys and men.  This might not seem a lot, but it can have a dramatic impact on the lives of those affected.  It’s a rare bleeding condition, caused by a hereditary lack of clotting factor VIII or IX.

Manchester is the third largest haemophilia centre in England, serving the North West of England

How frequently a person bleeds and the severity of those bleeds depends on how much circulating clotting factor the person has.  Those severely affected bleed frequently into joints and muscles leading to arthritis by early adulthood.

In the pre-treatment era, the life expectancy of severe haemophilia was 10–15 years. Now, with the introduction of clotting factor replacement therapies, outcomes for people with haemophilia are better than ever before.  Children with the condition can expect to have a similar life expectancy and quality of life to those without haemophilia.

Optimising treatment – the key challenge is being able to provide a sustained level of clotting factor

Replacement therapies require injections of blood clotting factors, either at the time of a bleed (on demand) or at regular intervals, as a preventative measure (between twice weekly and daily).  This can be inconvenient disrupting school, work and social commitments and is also expensive, costing over £100,000 per patient per year.

There are also a number of challenges around being able to consistently manage bleeding in people with haemophilia. They may:

• experience fluctuations in their levels of clotting factor putting them at risk of spontaneous (breakthrough) bleeding, which could lead to death or disability;
• exhibit an immune response to the clotting factor making it ineffective (neutralising antibodies occur in >30% of patients with Haemophilia A and 3% of patients with haemophilia B);
• as patients get older, they may suffer from crippling arthritis (associated with breakthrough bleeding episodes) or other age-related conditions that doctors have little experience of managing in this group.

One area of research Manchester is exploring, in collaboration with industry, is to extend the effectiveness of replacement therapies.  This is done either by creating a longer acting factor VIII or XI concentrate by or introducing an antibody to activate the clotting mechanism indirectly.

Can gene therapy cure haemophilia?

Another approach is whether gene therapy can replace the deficient gene in haemophilia with a working version so that the patient starts to make their own factor VIII or IX preventing further bleeding.  Gene therapy could normalise the quality of life for those affected – potentially through a ‘once-in-a-lifetime’ injection that completely eliminates the need for frequent injections of clotting factor replacement therapy and avoids the development of haemophilic arthritis.

In gene therapy studies, we are looking for sustained production of clotting factor (evidence that the healthy gene is working), so studies have focused on severe patients where it’s easier to measure a difference.  The gene is delivered through injection of a viral vector – the inactive outer coat of a virus which specifically targets the liver, which is packed with the normal factor VIII or IX gene. The vector is a sort of delivery system, which delivers the normal gene to liver cells which, once transfected, start to synthesise the missing clotting factor.

Each study participant’s response to treatment must be carefully monitored for adverse events.  Usually they attend an appointment twice weekly for 12 weeks at our onsite NIHR Manchester Clinical Research Facility.  One adverse reaction we look for is an immune response to the vector or gene, which kills the liver cells receiving the vector meaning that the gene is unable to synthesise the clotting factor protein.

So far, results from trials focusing on haemophilia B (IX deficiency) look promising with some studies progressing to phase 3 and we’re due to start a gene therapy trial in haemophilia A (VIII deficiency) soon at Manchester Royal Infirmary.

I’m excited that our patients have the opportunity to trial this cutting edge technology in Manchester.  But, as you can see that we are on a journey in terms of generating the evidence to prove that gene therapy is safe and effective. There are also practical considerations around how a ‘once-in-a-lifetime’ gene therapy (vs. regular replacement therapy) would be funded by the NHS.

Written by Professor Charles Hay.