BioEd Online

Scientists in Germany are trying to establish what exactly caused the death of a 28-year-old patient participating in a gene-therapy trial based in Frankfurt.

He was one of three patients recruited so far to the trial, which aims to treat the rare but life-threatening immunodeficiency condition known as chronic granulomatous disease. He died on 10 April of septic shock, which caused his internal organs to fail.

Scientists reported the death at the annual meeting of the German Society of Internal Medicine on 26 April. The researchers say they think the death was not caused directly by the replacement gene given in the therapy, but they will investigate the question.

Chronic granulomatous disease is a devastating condition caused by a defect in a gene called gp91phox. The disease leaves its victims vulnerable to incessant bacterial and fungal infections, but they can fight viral infections. Few sufferers survive childhood.

During the gene therapy, doctors first extracted some bone marrow cells from the patients and inserted a working copy of the gp91phox gene. They then killed off remaining bone marrow cells in the patients using chemotherapy, and replaced them with the treated cells.

The deceased patient underwent gene therapy in January 2004, and until the end of last year was enjoying a life without hospitalization. The other patients in the trial, one who was treated in Frankfurt in May 2004 and a third who was treated in Zurich in May 2005, are also now able to enjoy a normal life without repeated, severe infections. A report earlier this month on two patients suggested that the trial was so far a success¹.

Cancer trigger

Gene therapy has had its share of problems. In trials to treat another inherited immune system disease, known as severe combined immunodeficiency (SCID), three patients developed leukemia from the treatment. It has since been realized that the replacement gene sometimes inserts itself next to genes that can cause cancer, called proto-oncogenes.

The Frankfurt scientists had been closely monitoring their patients for symptoms of leukaemia-like disease and found none. The gp91phox gene can also insert into proto-oncogenes, but this had not caused cancers in animal tests; and in the patients it seemed to improve the efficacy of the therapy because it made the treated cells multiply unusually fast once they were in the body.

The death "was definitely not a direct consequence of the transferred gene," says Manual Grez, the molecular virologist at the Institute for Biomedical Research, Frankfurt, who led the scientific side of the trial.

Indirect effects

But Grez says that an indirect effect of the gene-therapy strategy might have contributed to the death. One possibility is that the number of working gene-modified cells had fallen to low levels so that the body could no longer fight infections.

Another possibility is that the chemotherapy that patients received may have destroyed cells that help to fight viral infections, to which chronic granulomatous disease patients normally have defences. "But we are still in the realm of speculation," says Grez. "We won't know anything for sure until we have results of all the tests, which could take weeks."

The tests involve determining the number of working gene-modified immune cells that were remaining in the patient's blood, and analysing the general spectrum of the immune cells. Tests are also being done to determine precisely what sorts of bacterial or viral infections were present in the patients. "We must understand the pathology exactly," says Grez.

Klaus Cichutek, head of gene therapy at the Paul Ehrlich Institute, the German regulatory authority based in Langen, says that the "tragic death" is not a major setback to the field. "It is a very steep road to good gene therapy," he says, "and gene therapy is one of the few hopes that such patients have."

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