Gene therapy comes of age with the saving of a little girl's life

An international team of doctors passed another milestone in medical history yesterday, curing a two-year-old girl of an inherited disorder of the immune system using revolutionary gene therapy.

The girl, an Arab-Israeli called Salsabil from Jerusalem, was born without an immune system and would almost certainly have died within months of birth without the treatment. Now she is normal and healthy, in effect cured of one of the most feared genetic diseases.

Her survival is living testament to the growing realisation that gene therapy may have come of age after many years of false hopes. Doctors throughout the world are growing increasingly confident about the future of gene therapy, a technique where "healthy" genes are injected into a patient to replace their defective DNA.

Salsabil was born in February 2000 into a family with a history of a gene disorder known as severe combined immunodeficiency (SCID), often called bubble baby syndrome because victims must be kept in a sterile environment.

One of Salsabil's siblings had died of the disease and an older sister, Tasmin, had survived only after a transplant of blood cells from the umbilical cord of a younger, unaffected brother. Unfortunately for Salsabil, there were no suitable donors for either a bone-marrow transplant or for stem cells from the umbilical cord blood. At seven months of age doctors decided gene therapy was the only option.

The team was led by Professor Shimon Slavin, Shoshana Morecki and Memet Akar of the Hadassah-Hebrew University Medical Centre in Jerusalem. They worked with Claudio Bordignon and colleagues at the San Raffaele Institute for Gene Therapy in Milan.

Israeli surgeons extracted bone marrow from Salsabil and mingled the cells with a genetically engineered virus containing a healthy copy of the affected gene. The virus, engineered to be harmless, automatically injects the human gene directly into the nucleus of the bone-marrow cells.

Before the doctors transfused the bone marrow back into Salsabil, they performed a radical procedure to increase the chances of the technique working. They subjected Salsabil to a mild form of chemotherapy – called non-myeloblative conditioning – to suppress her defective bone marrow cells and prepare the ground for the transfused cells to multiply.

Dr Bordignon said: "Non-myeloblative conditioning means you don't really wipe out the bone marrow, you just give one of the drugs used for a transplant, at a much lower dose, to make 'space' for engineered marrow to seize, expand and grow better."

It worked. Within weeks of having a transfusion of her own marrow, Salsabil began to show signs of recovery. The infused stem cells migrated naturally to her bone marrow and began making several of the key cells of the immune system, such as the white blood cells known as B and T lymphocytes. Within months, Salsabil began making her own antibodies for the first time, when before she had to rely on those in her mother's milk. She responded normally to a tetanus vaccine and even survived chickenpox.

Within a year she had shrugged off the respiratory infections, chronic diarrhoea and scabies that had plagued her since birth. She was allowed home and needed no treatment. She was effectively cured of a disease written in her genes.

"I would call this a cure," Professor Slavin said. "We have achieved 100 per cent replacement of her defective bone marrow cells. She is a cute little girl. The concept can be applied to all genetic diseases where there is a need to engineer stem cells to produce normal products, especially when patients have no matched donor available for safe bone marrow transplantation."

It is not the first time that doctors have cured SCID children with gene therapy, but it is the first time a child has been cured of such a complex form of the disease. Salsabil suffered from a lack of an enzyme called adenosine deaminase (ADA), which results in a number of abnormalities of the immune system and is considered the most complex and most difficult SCID to treat.

W French Anderson of the University of Southern California, who was the first to try to treat ADA deficiency by gene therapy, said yesterday the Italian-Israeli study was an important advance for the entire concept of gene therapy.

"This gives a boost to the whole field because it proves our basic premise, that if you can get enough gene- engineered cells into the patient it will cure the disease," he said. "That is very important and this is very exciting."

It was not always so. After the initial hype that heralded the first gene therapy attempt by Dr Anderson in 1990, the prognosis did not look good. Gene therapy alone did not cure in the way it was meant to and two little girls – Ashanthi deSilva and Carly Todd, the first gene therapy patients in America and Britain respectively – had to rely on more conventional treatment to survive.

"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," Dr Anderson said. "Then we realised that nothing was really working at the clinical level."

The worst moment came in September 1999 when an American patient called Jesse Gelsinger died after a gene therapy injection into his liver. No one knows for certain why he died, but it may have been linked to the virus used in the experimental procedure.

It was a development that was carefully monitored by Britain's gene therapy advisory committee, experts responsible for overseeing all UK gene therapy trials. Scientists had to redouble their efforts to ensure the safety of any viruses used in the many and varied trials, which included attempts at treating cancer with genetically modified cells as well as treatments for some of the 4,000 or so inherited disorders caused by a single defective gene, from cystic fibrosis to haemophilia.

Finally, in April 2000, scientists in France reported their first unequivocal success with gene therapy – on children with another form of SCID. This year, doctors at the Institute of Child Health at Great Ormond Street Hospital in London reported similar success on an 18-month-old called Rhys Evans who had an SCID caused by a defect in the "gamma c" gene.

Today Rhys is a healthy two-year-old with no signs of the inherited disorder that had confined him to the solitary world of an antiseptic hospital room. Like Salsabil, he mixes freely with other children – an activity that might have killed them both before the treatment – and he now lives the normal life of any toddler. Adrian Thrasher, the consultant immunologist at Great Ormond Street who treated Rhys, said the research from Jerusalem was very encouraging for the treatment of immunodeficiency by gene therapy. He hopes the treatment may now be extended to cover other inherited illnesses. "There are more than 4,000 genetic conditions, and at least 80 different immune diseases alone," he said. "The technique will have to be worked out for each individual condition."

Treating diseased cells in the bone marrow is technically easier than treating the defective genes of, say, nerve tissue or heart muscle.

Although gene therapy has now proved effective in curing one or two diseases, nobody can yet be sure that such treatment can be made to work in each of the thousands of genetic disorders affecting children.