Gene therapy's new lease of life

Scientists said it would cure all ills - but they couldn't make it work. Now, finally, gene therapy is notching up some notable successes, says Steve Connor

When a little girl called Ashanthi DeSilva became in September 1990 the first person in the world to be treated with the revolutionary technique of gene therapy, the optimism of everyone involved was palpable. Gene therapy was going to cure the previously incurable, it would rid humanity of many of the most distressing diseases and banish the belief that we are always going to be the hapless victims of our wayward DNA.

Gene therapy, where "healthy" copies of a gene or strand of DNA are inserted into the body, was going to correct inherited defects and metabolic disorders, as well as provide new avenues for treating lethal diseases such as cancer. With the decoding of the human genome, gene therapy was going to open the doors to the treatment of any disorder involving errors buried deep within the chromosomes. All it would take is to splice a corrected gene into our defective DNA.

It was, of course, almost total hype. Since 1990, there have been about 500 clinical trials worldwide involving gene therapy, and the vast majority have so far proved less than successful. Ashanthi is still doing well today but doctors believe that this is probably more to do with the drugs she takes than the gene therapy. Britain's first gene-therapy operation, on toddler Carly Todd in 1993, when she was 17 months old, also proved disappointing, although Carly is now doing well after conventional treatment and a bone-marrow transplant.

The reality is that it has been an uphill struggle to get gene therapy to work. "There was initially a great burst of enthusiasm that lasted three, four years where a couple of hundred trials got started all over the world," says gene-therapy pioneer W French Anderson, who led the team at the US National Institutes of Health that treated Ashanthi. "Then we realised that nothing was really working at the clinical level."

And that was before tragedy struck in September 1999, when a young American called Jesse Gelsinger died after a gene-therapy injection into his liver. No one is sure exactly why he died four days after the injection. It seems his immune system launched a raging attack on the adenovirus "vector" that scientists used to carry the corrected genes into his liver. After that, he suffered an overwhelming cascade of organ failures, starting with jaundice and progressing to a blood-clotting disorder, kidney failure, lung failure and ultimately brain death.

It was perhaps the lowest point in the history of gene therapy, and questions were raised not just about whether it would ever work, but whether it would ever be safe.

Over the past two years, however, gene therapy has begun to experience a renaissance. In April 2000, a team of French scientists published information showing unequivocally for the first time that gene therapy could correct Severe Combined Immune Deficiency (Scid) disease in young children. Four months after that, American doctors said they had halted the growth of head and neck tumours using a form of gene therapy. More recently, scientists have reported that they have repaired the gene behind Duchenne Muscular Dystrophy, albeit only in an experiment on laboratory mice.

But perhaps the most exciting success recently has been in the treatment of haemophilia, one of the first diseases shown to have a genetic basis. Everyone involved in gene therapy is watching this particular clinical trial with intense interest because haemophilia is seen as the standard on which the entire edifice of gene therapy could stand or fall. "It's a fantastic model for other inherited conditions," says Professor Christine Lee, head of the haemophilia centre at the Royal Free Hospital in London, where the first UK trial could soon begin.

Haemophilia, when the blood fails to clot, is caused by a gene defect that prevents the production of clotting factors. It is a sex-linked disorder, affecting about one in every 5,000 baby boys. Patients can suffer badly from internal bleeding, especially around the joints. Haemophilia A, the most common form of the disease, is when factor VIII is lacking and haemophilia B is caused by a lack of factor IX.

Katherine High, a haematologist at the Children's Hospital of Philadelphia, and Mark Kay, a geneticist at Stanford University in California, have chosen to conduct gene-therapy trials on haemophilia B patients because the factor IX gene is slightly shorter than factor VIII and is therefore easier to insert into the viral vector.

The aim is to engineer a patient's genes enough for the patient to produce just 1 per cent of normal levels of factor IX. This sounds minuscule, but just this tiny amount of the missing factor is enough to restore the condition of the patients to a state that is far easier to control. "At 1 per cent clotting factor, [the patient's condition] changes from severe disease to moderate, which really increases quality of life of the individual," explains Kay. At 1 per cent, most of the joint damage and bleeding complications of the disease are prevented, and if gene therapy cannot deliver this extremely moderate increase in gene activity, what hope is there for other genetic diseases?

Initial results of the trial, where the first three patients had injections into thigh muscles, proved successful. Within two to three months the gene was making the factor IX protein, and two of the patients started producing at levels that enabled them to take fewer injections of the clotting factor itself. Most importantly, none showed any ill effects.

One of the important aspects of the trial was the type of vector used to carry the gene into the patient's cells. Instead of using the adenovirus (a common cold virus) that was implicated in Gelsinger's death, the scientists used adeno-associated virus (AAV). Unlike adenovirus, AAV does not appear to stimulate the human immune system, which is why it is considered safer.

As more patients were recruited to take part in the trial, Kay and High planned the next phase of the experiment – direct injection of the AAV and the factor IX gene into the patient's liver. This is expected to result in a significant boost in factor IX levels. However, this part of the trial came to an abrupt halt last October when the researchers detected AAV in the semen of some of the patients.

This raised fears that genetic alterations might also be taking place inside the sperm cells, which is forbidden in the US (and the UK) because of concerns that it could lead to "germline" gene therapy, when the DNA of subsequent generations is altered artificially. However, further research showed that the viral genes had not penetrated the sperm cells and that the virus is eventually cleared from the semen.

The US Food and Drug Administration has now allowed the trial to continue, and last week Professor High prepared to inject the altered genes into the second patient's liver. "Discovering the AAV vector in the semen appears to be a shedding phenomenon and after a while it should wash out," says Professor High.

This is good news for scientists in the UK, who are watching the experiment closely with a view to setting up a similar trial in Britain. Professor Lee at the Royal Free says she has already made tentative approaches to the UK's regulatory agency, the Gene Therapy Advisory Committee (GTAC). "I do expect trials to come here, but quite when that's going to happen is not entirely clear," Professor Lee says. "My guess is that certainly in the next five years we'll be participating in trials, but I feel a little conservative about the time it will take for it to become mainstream treatment."

There are still many problems to overcome, especiallythe residing fears over germline gene therapy. Professor Norman Nevin, the chairman of GTAC, said that one of the guiding principles on which the committee makes decisions is that there is little or no risk of altering the genes of sperm or eggs. "At the present state of the art I am certain that the GTAC would not consider a project that would carry a high risk of germline transmission," Professor Nevin says.

The American regulatory agency is insisting that Professor High's trial makes regular and detailed analyses to ensure that germline alterations do not occur unwittingly. However, it is not an approach that everyone agrees with. Eric Jüngst, a bioethicist from Case Western Reserve University in Cleveland, Ohio, argues that such an accidental change could be a boon for those in favour of germline gene therapy.

As he says: "If by chance one of these accidents did effect a germ-line cure, it would be an awfully powerful selling point for those who say we should be taking that position from the beginning." If gene therapy is shown to work on patients today, perhaps we can do something similar to cure the patients of tomorrow who have yet to be born.