Bad genes

It has been a bad few months for the pioneers of gene therapy. The frontier medical technology has been in the news for the wrong reasons. A little over a decade ago, when the first gene therapy trials involving human subjects were sanctioned, the more optimistic scientists and biotech investors hoped that by now the first effective treatments for previously incurable diseases would have appeared on the horizon.

It hasn't happened. Not one of the hundreds of past or present gene therapy experiments has yet turned up anything resembling a cure. And a series of disturbing revelations from the US, following the death last September of one gene therapy guinea pig, 18-year-old Jesse Gelsinger, has exposed the entire field to accusations of negligence, expediency and putting profit before safety.

The response of gene therapy's backers - dogged researchers, biotech firms and thousands of people desperate for sick and dying family members to have their raised hopes met - is the same: be patient, and don't damn the whole programme over the reckless behaviour of a few US scientists.

Gene therapy covers a multitude of techniques with one thing in common. They all involve manipulating a cloned version of a naturally-occurring gene and introducing it into the human body in order to combat a disease.

The techniques have something else in common: they are all extremely difficult. The principle is simple enough - often, it is a case of trying to replace abnormal genes in a patient with normal ones. The very vocabulary used to try to explain the process for lay people, filled with words like "delivering" genes and "packaging" genes, makes it sound like a straightforward postal operation. The reality is more extreme - something like trying to replace a single component in all the cars and trucks in a city a thousand miles away while the vehicles are moving.

There are between 5,000 and 8,000 diseases, ranging from the well-known such as cystic fibrosis to obscure ailments affecting a handful of people, for which a defective gene or set of genes is responsible. As scientists first began to tie particular gene mutations with particular illnesses, hopes soared that a way would be found to swap faulty genes for good ones. The hopes remain, but they have now been tarnished by experience.

Cystic fibrosis seemed like one of the prime candidates for successful gene therapy, and since the defective gene was identified in 1989, about 150 volunteer sufferers - including dozens in the UK - have been administered with doses of "proper" genes. On a molecular level, researchers measured slight, short-term improvements, but as one commented last year: "A cure is not around the corner." The problem is getting the replacement genes to the cells in the lungs that are malfunctioning. The disease generates a thick mucus that forms a barrier to delivery, which is often by means of a spray.

"Thus far, the level of correction hasn't been strong enough or lasted long enough to get clinical benefits," says Dr Martin Scott of the Cystic Fibrosis Trust in the UK.

The difficulty of getting "good" genes to the place in a patient's body where they are needed, and the sheer frustration of researchers at the slow pace of research, seems to have been behind Gelsinger's death.

Scientists at the previously respected Pennsylvania Institute for Gene Therapy violated a string of federal and in-house rules to recruit and use the unsuitable Gelsinger as a volunteer in their studies of gene therapy treatment for a liver disorder. And they used a particularly risky technique of delivering the "good" genes - putting them inside a modified cold virus and injecting it into Gelsinger's bloodstream.

Last month federal regulators shut down all the institute's gene research trials. Last week, it emerged that 652 out of 691 cases of "serious adverse events" in US gene therapy trials had not been properly reported. Most of those whose illness worsened or who died were terminally ill. But there is concern that, in the US at least, commercial pressures on scientists to get results is leading them to use the inevitable deaths of guinea pigs as an excuse to cut corners.

In Britain, scientists seeking to carry out gene therapy research on patients have to get permission from two agencies - the gene therapy advisory committee, GTAC, and the medicines control agency, the MCA.

Since it was set up in 1992, GTAC has consented to 40 gene therapy studies, involving 260 volunteers, most of them linked to treatment for cancer. Researchers are required to report to GTAC on any death or deterioration in a trial patient's condition whether the gene therapy itself was thought to be the cause or not.

A department of health spokesman says there has never been "unexpected serious side effects" from British gene therapy trials. None of the British gene therapy studies has used the method tried by the Pennsylvania researchers, although viruses have been used as packages to get genes to their destination. Indeed, many of the British scientists have less ambitious aims than that of actually replacing faulty genes with working ones.

In Glasgow, they are trying to treat head, neck and ovarian cancer by modifying a virus's own genes to turn it into a cancer killer. At Guy's Hospital in London, trials have been completed in a four-country study of gene therapy for breast cancer. The idea is to give patients injections of a virus modified to carry two human genes. One gene labels tumour cells as enemies; the other marshals specialist cells to destroy them.

A British biotech company, Oxford Biomedica, is funding research at the Churchill Hospital in Oxford into what are called "prodrugs". Again, the aim is not to replace faulty genes, but to use genes as part of treatment - in this case, to trigger an anti-cancer chemotherapy drug exclusively in a tumour, rather than having it reach the tumour after travelling through the rest of the body first.

The work at Guy's and the Churchill highlights the irony of gene therapy's current stained reputation - that up until now, whether it worked or not, it has always seemed like a relatively safe, uncomplicated treatment. As one researcher put it, "Patients love it." Compared to standard chemotherapy drugs, which provoke side effects like baldness and nausea, the quick injection or spray of a gene therapy medium is a breeze. The question is whether some researchers did not become too casual in their assumption that delivery of the genes was always going to be harmless.

But British scientists insist that, whatever happened in the US, it isn't happening here. "We have a very high level of monitoring and control," says Oxford Biomedica's chief executive, Dr Alan Kingsman. "The important thing to get out of what's happened in the US is that the bad things which have happened there are much more to do with procedure than with the technology. What we really must not do is sacrifice the field because of bad procedures in the US."

The inherited diseases that gene therapy could cure

Cystic fibrosis

Affects about 7,000 people in the UK. One in 25 people is a carrier of the faulty gene. The disease causes a thick mucus to build up in the lungs which, along with other symptoms, impairs breathing. Medical improvements have pushed average survival age up to adulthood, but the disease still cuts life drastically short, usually from respiratory failure.

Muscular dystrophy

A family of disorders caused by abnormal genes. The most common form affects about one in 15,000 male births. Muscles progressively waste away, with death normally in the late teens or early 20s. Identification of the gene responsible has made diagnosis straightforward even before symptoms develop but scientists are wary of seeking a gene therapy to treat it; it appears that working genes would somehow need to be introduced into every affected cell, a daunting task.

Huntington's disease

About one in 10,000 people have the faulty gene that causes this degenerative nerve disease. It usually appears between the ages of 35 and 40. Involuntary muscle movements and dementia usually lead to death within 10 years.


A disease that prevents normal blood clotting, causing a major crisis even from the most minor injury. The defective gene that causes the disease is passed by father to daughter; the daughter doesn't suffer from it, but becomes a carrier. Researchers have recently announced encouraging results from gene therapy trials to combat haemophilia.

Epidermolysis bullosa

One of thousands of extremely rare genetic disorders waiting for a gene therapy miracle, the faulty gene here fails to hold skin together properly. Skin comes off when rubbed; parents cannot pick up their children. One in every 20,000 UK babies is affected.

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