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|1|2 Five children with a genetic disease that wipes out their immune system have successfully been treated with gene therapy
Editorial: "Gene therapy needs a hero to live up to the hype"
MOST parents dream of a 5-week-old baby who sleeps through the night, but Aga Warnell knew something was wrong. Her baby, Nina, just wasn't hungry in the way her other daughters had been.
Within weeks, Nina became very ill, says her father, Graeme. She was admitted to hospital with a rotavirus infection. Then she picked up pneumonia.
It turned out Nina had a condition called severe combined immunodeficiency (SCID). She had been born without an immune system due to a genetic defect. It is also known as "bubble boy" disease, since people affected have to live in a sterile environment. "The doctors said 'you need to prepare yourself for the fact that Nina probably isn't going to survive'," says Graeme.
A year-and-a-half later, Nina is a happy little girl with a functioning immune system. She has gene therapy – and its latest improvements – to thank for it.
SCID was the first condition to be treated with gene therapy more than 20 years ago. A virus was used to replace a faulty gene with a healthy one. But in subsequent trials, four young patients were diagnosed with leukaemia two years after receiving a similar treatment. An 18-year-old also died following a reaction to a virus used in gene therapy for a liver condition. It was the start of a rocky road (see "Trials and tribulations of gene therapy").
Gene therapy has come a long way since, and Nina's case, along with others, mark a turning point: researchers seem to have found a safer way of manipulating our genes.
Preliminary results for the first two children to receive the improved SCID gene therapy – 18 months ago – were presented at the European Society of Gene and Cell Therapy conference in Madrid, Spain, last week. The children's immune systems have continued to improve since receiving the treatment, says Bobby Gaspar of Great Ormond Street Hospital in London, who led the trial.
Three further children – including Nina – have been treated since then, and they too are showing signs of a full recovery.
All five had a form of the disorder called ADA-SCID, caused by a faulty gene for adenosine deaminase. This enzyme usually dispatches a toxic molecule from white blood cells. In its absence the toxin builds up, killing the cells that fight infections.
Stem cells were harvested from Nina's bone marrow and given a working version of the ADA gene, before being injected back in. That was in April, and she wasn't expected to show much of an improvement before December. But by August her white blood cell count had nearly doubled, and today she has the immune system of a healthy newborn baby.
"At last, the successes are beginning to be more than the failures," says Inder Verma at the Salk Institute in La Jolla, California. "All of the hard work has come to a point where gene therapy could become a more routine modality of medicine."
The concept of gene therapy is simple: insert a working gene into a person with a faulty version, and its product should overcome the defect. But the reality is more complicated, because you need something to integrate the gene into the patient's DNA and persuade the cells to read it. In other words, you need a vector.
Viruses are the obvious choice as they survive and spread by inserting their genes into the host's genome. Retroviruses work like this, so were the first choice for the initial gene therapy trials. The problem is that they insert genes at random locations in the genome, as well as inserting regulatory sequences that can sometimes activate nearby genes and trigger cancer.
To overcome this, researchers have turned to lentiviruses. These still insert genes randomly, but can be modified to disable some regulatory sequences. "The new generation of lentiviral vectors is much safer, although the risk is not zero," says Patrick Aubourg at the French National Institute of Health and Medical Research in Paris. "However, we don't use gene therapy to treat a toothache, we try to treat diseases which result in early death."
Earlier this year, three children with a degenerative enzyme disorder were successfully treated using a modified lentivirus, along with three with an immune disorder called Wiskott-Aldrich syndrome. Promising results have also been seen in degenerative disease adrenoleukodystrophy and the blood-cell disorder beta-thalassaemia. Around 700 gene therapy trials using lentiviruses are ongoing.
Other vectors are showing promise too. For example, adeno-associated virus (AAV) doesn't insert its genes into the genome, but places them alongside it, meaning they get read but are not passed to subsequent generations of cells. That is a problem if you are interested in relatively short-lived cells, like immune cells, but not if you want to modify neurons or liver cells, which last decades.
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(Image: Stephen Hicks) 
