By Robin McKie
The Observer, Sunday 2nd October 2016
Scientists to begin trials for treatment to overcome inherited disease that affects 300,000 newborn babies a year
Scientists are finalising plans to use gene therapy to treat one of the world’s most widespread inherited diseases – sickle cell anaemia. The technique could begin trials next year, say researchers.
About 300,000 babies are born globally with sickle cell disease. The condition causes red blood cells to deform, triggering anaemia, pain, organ failure, tissue damage, strokes and heart attacks. In the west, patients now live to their 40s thanks to the availability of blood transfusions and other treatments. But in Africa most still die in childhood.
“We have known exactly what is the cause of sickle cell anaemia for 60 years, but it has been enormously difficult to turn that information into a treatment,” said Prof Stuart Orkin of Harvard Medical School. “There are a million steps between the lab bench and the clinic, it turns out. However, I think we are closer.”
Sickle cell anaemia is triggered by a genetic fault that changes one of the dozens of amino acids that make up haemoglobin, the key constituent of the red blood cells that carry oxygen around our bodies. The mutated haemoglobin undergoes a change in shape and blocks veins.
The condition is carried by symptomless parents and is thought to have arisen in Africa, the Caribbean and other areas as a protection against malaria. However, when two carriers have children there is a one-in-four risk a child will inherit two sickle cell genes, one from each parent, and develop the disease. In Britain a screening service is offered to parents. Nevertheless more than 300 affected children are born every year.
Crucially, not every person with sickle cell disease succumbs to the condition, scientists have found. Some appear to be protected against its ravages. “We have two types of haemoglobin,” explained Orkin. “There is foetal haemoglobin whose production is normally switched off when we are born. Then the standard adult version takes over.”
But in some individuals foetal haemoglobin production is not turned off at birth. “Those individuals are supplied with foetal haemoglobin throughout their lives and for those who also inherit sickle cell anaemia this protects them against the disease by making a substance that can carry oxygen round the bodies,” he said. “We have calculated that you only need to make a small amount of foetal haemoglobin to halt sickle’s symptoms.”
The prospect of boosted foetal haemoglobin levels in patients was helped when it was found that a gene called BCL11A acts as a suppressor of foetal haemoglobin production. “Essentially, it switches off foetal haemoglobin’s manufacture after birth,” said Orkin. “What we aim to do is to stop it doing this. We want to suppress the suppressor and allow foetal haemoglobin to continue to be made in the body.” And crucial to this task was the discovery by Orkin and colleagues that a small piece of the BCL11A gene, called the enhancer, controls foetal haemoglobin expression.
“We can now use gene-editing technologies to cut out that little enhancer so that the BCL11A gene stops shutting down foetal haemoglobin production and allow children with sickle cell disease to start making it in their blood,” added Orkin. “Essentially, we will take bone marrow – where blood cells are made – from a patient, gene-edit it so that those cells produce enhanced levels of foetal haemoglobin, and return them to that patient.”
Orkin said the science had now been worked out. “We hope to begin trials in the near future.” He added that several other centres in the US were gearing up to start gene therapy trials for sickle cell using similar approaches.
David Williams, of the Boston Children’s Cancer and Blood Disorders Center, is using a slightly different technique to boost foetal haemoglobin but also hopes to begin trials next year. “When you knock BCL11A down, you simultaneously increase foetal haemoglobin and repress sickling haemoglobin, which is why we think this is the best approach,” said Williams.
Such treatments were only like to help patients in the west, Orkin acknowledged. “What we need is a pill that will boost foetal haemoglobin in patients, one that is simple to administer,” he said. “That is our ultimate goal, and the lessons we learn from our gene therapy work will help us get there. Once we do that we can then say we have conquered sickle cell.”