Haemophilia B: Gene therapy trial shows early success in people with blood-clotting disorder

In a small study of 10 people with haemophilia B, nine were still forgoing the condition’s standard treatment about two years after receiving a single gene therapy injection

By Jason Arunn Murugesu

A form of gene therapy has shown initial success in treating a rare form of haemophilia, but whether the treatment will be effective in the long term is unknown.

Haemophilia B is a rare genetic condition that prevents blood from clotting effectively, sometimes causing life-threatening bleeds. It occurs due to a genetic mutation in the X chromosome that leaves people unable to produce sufficient levels of the protein factor IX, which is crucial for blood clotting.

It is currently treated by regular injections, usually weekly, of laboratory-produced factor IX. Despite this treatment, some people continue to have debilitating joint damage.

To test the potential of gene therapy to correct this genetic fault, researchers at University College London, the Royal Free Hospital in London and the biotechnology company Freeline Therapeutics infused 10 adult men experiencing haemophilia B with a single dose of a treatment called FLT180a, administered via an adenovirus-associated virus.

Any form of haemophilia is far more common in males than females as the latter carry two X chromosomes and therefore only experience the condition if both their chromosomes are affected or if one chromosome is missing or non-functioning.

Twenty-six weeks after the gene therapy was administered, all the participants had increased factor IX levels, which varied according to the gene therapy dose the individual received.

About two years later, this response was sustained in nine of the 10 participants. At the start of the study, all the men had factor IX levels of 2 per cent or less of what is considered normal. At their last reported check-up, this ranged from 23 per cent to 260 per cent in the nine participants, depending on their gene therapy dose.

Moreover, the nine participants no longer needed to undergo their previous treatment regimen of factor IX injections.

“Removing the need for haemophilia patients to regularly inject themselves with the missing protein is an important step in improving their quality of life,” Pratima Chowdary at University College London said in a statement.

This form of gene therapy uses a packaging from the proteins found in the outer coat of the adenovirus-associated virus to deliver a functional copy of a gene directly to an individual’s tissues, compensating for the gene that isn’t working properly, according to the researchers. Newly synthesised proteins are then released into the blood.

The participants will be followed for 15 years in total. “The long-term follow-up study will monitor the patients for durability of expression and surveillance for late effects,” said Chowdary.

Based on the evidence so far into this type of gene therapy, John McVey at the University of Surrey in the UK thinks the participants’ factor IX levels will drop in the long term. In addition, people cannot receive this specific gene therapy with the same type of viral vector more than once.

“The body might recognise it [the viral vector] as foreign and increase antibody levels, which immediately bind to the virus and neutralise it,” says McVey.

The therapy also requires participants to regularly take immunosuppressants to ensure their body doesn’t reject FLT180a. Long-term use of immunosuppressants has been linked with an increased infection risk. McVey says it is unclear how long the participants will need to be on immunosuppressants.

Of the reported adverse events in the study, about 10 per cent were related to the gene therapy and 24 per cent to immunosuppression. A serious blood clot occurred in one of the participants who received a high dose.

Overall, McVey says the findings are encouraging: “There’s a lot of work to be done but it’s very promising.”

“There’s a big difference between one injection that cures you for a particular length of time compared to replacement therapy – which is what we use now – that requires injections at least once a week for the whole of their lives,” he says.

Journal reference: New England Journal of Medicine, DOI: 10.1056/NEJMoa2119913