Many rely on blood transfusions

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By Andy Coghlan

A TEENAGE boy with an inherited disease that affects millions worldwide seems to have been cured using gene therapy. The treatment appears to have stopped the painful symptoms of sickle cell disease, demonstrating the potential for gene therapy to treat common genetic diseases.

All the blood tests we performed show that the teenager has been cured of sickle cell disease

The idea of gene therapy using strands of DNA to compensate for a persons malfunctioning genes is almost three decades old. However, the approach has so far mostly been used to treat very rare diseases (see Long road to success). In contrast, sickle cell disease affects 100,000 people in the US alone. If the treatment proves successful in larger trials, it could bring gene therapy into widespread use.

It could be a game changer, says Deborah Gill at the University of Oxford. The fact the team has a patient with real clinical benefit, and biological markers to prove it, is a very big deal.

People with sickle cell disease make abnormal versions of haemoglobin, the blood protein that carries oxygen around the body. This can be caused by mutations in the gene that makes a subunit of haemoglobin, called beta-globin. The mutations cause haemoglobin to clump together, distorting red blood cells into a sickle-shape that can get stuck in blood vessels around the body.

People with the disorder are given blood transfusions to clear these painful blockages and prevent new ones. Bone marrow transplants can treat the disease, but matching donors can only be found for around 10 per cent of people with the condition.

Now a team in France seems to have developed a treatment that would work for everyone with the disorder. First, the team took bone marrow stem cells from the boy when he was 13, and gave them extra, mutated versions of the gene that codes for beta-globin. These were designed to make beta-globin that would interfere with the boys faulty proteins, stopping them from clumping together.

The researchers then put these stem cells back into the boys body. After around three months, he began producing large quantities of haemoglobin that behaves normally (New England Journal of Medicine, DOI: 10.1056/NEJMoa1609677). The patient is now 15 years old and free of all previous medication, says Marina Cavazzana at the Necker Childrens Hospital in Paris, who led the team. He has been free of pain from blood vessel blockages, and has given up taking opioid painkillers.

Cavazzana is confident these benefits will last. All the tests we performed on his blood show that hes been cured, but more certainty can only come from long-term follow-up. She says her team has treated seven other patients, who are showing promising progress.

We are all very excited by the work, and this success provides support for this and other genetic strategies targeting this horrible disease, says John Tisdale at the US National Heart, Lung, and Blood Institute in Maryland.

David Williams, at Boston Childrens Hospital in Massachusetts, suggests that the boy may still occasionally experience blockages, because his own original genes are still able to produce faulty haemoglobin. Its important to see what happens over time, and how many other patients see similar benefits.

However, should the gene therapy prove to be effective in larger trials, its expense may limit its use to richer nations. We should be realistic in remembering that there are hundreds of thousands of sickle cell patients in less developed countries, and that the therapy is not easily exportable or adaptable to countries with less well-developed health systems, says Stuart Orkin at Harvard Medical School.

Twenty years ago, gene therapy was touted as a cure for everything from cancer to cystic fibrosis. Now it is finally starting to fulfil its promise.

In 2012, Glybera became the first gene therapy to be approved, for people with a rare disorder that makes them unable to process dietary fat. Last year, the first commercial gene therapy that alters a persons DNA was approved for children with a severe immune disorder. Gene therapies for rare forms of blindness are also showing promise.

But these conditions all affect very small numbers of people. Research into sickle cell disease (see main story), beta thalassaemia, haemophilia and cystic fibrosis mean gene therapy may not be too far from becoming mainstream medicine for the most common genetic diseases.

This article appeared in print under the headline Gene therapy breakthrough

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