Edition: U.S. / Global

Patient Dies During a Trial Of Therapy Using Genes

Published: September 29, 1999

A patient has died while undergoing gene therapy in a trial study at the University of Pennsylvania in Philadelphia.

If the treatment itself should prove to be the cause of his death it would probably be the first by someone undergoing gene therapy and could be a severe setback for the experimental technique, whose fulfillment has long fallen short of its high promise.

The patient, Jesse Gelsinger, was an 18-year old from Arizona who suffered from a genetic defect that prevents the correct metabolism of ammonia. He was part of a group of 18 patients who were being tested with different doses of a virus carrying a corrective gene. He and another patient, who was unaffected, received the highest dose being given in the trial.

Mr. Gelsinger died on Sept. 17, four days after a dose of genetically engineered virus was injected into one of the main arteries of his liver, so as to deliver the highest possible dose of a corrective gene to the cells where it was needed.

The virus, known as adenovirus, is one of the causes of the common cold and usually causes only a mild fever. It has been used in many previous gene therapy trials. Mr. Gelsinger's death was first reported in Tuesday's editions of The Washington Post.

''We're all devastated by this,'' said Rebecca Harmon, a spokesperson for the University of Pennsylvania. ''Jesse truly was a hero in advancing the cause of science.''

Ms. Harmon said Mr. Gelsinger's was the first death to have occurred among the 130 patients who have been treated at the university's Institute of Gene Therapy. The institute, headed by Dr. James M. Wilson, is one of the leading gene therapy centers in the United States.

Dr. Steve Raper, the principal scientist in charge of the trial, said that the timing of the treatment and Mr. Gelsinger's death suggested a possible relationship but that the cause had not yet been determined.

''The major impact of Jesse's sacrifice,'' Dr. Raper said, is that safer viruses may need to be developed. ''Gene therapy,'' he said, ''still holds tremendous promise for a variety of diseases.''

To get corrective genes into cells, gene therapists have to rely on viruses, which specialize in exactly this task.

Adenovirus is used partly because it causes such a mild gene. Results have been generally disappointing, however, because the body's immune system usually roots out and destroys the virus after six weeks, along with the beneficial genes it has inserted. Well before Mr. Gelsinger's death, gene therapists had been trying to develop more suitable viruses as vectors.

Mr. Gelsinger's disease, ornithine transcarbamylase deficiency, is usually inherited but Mr. Gelsinger had a rare form in which his gene mutated after birth.

Mr. Gelsinger's father, Paul Gelsinger, 47, a licensed handyman in Tucson, Arizona, said his son became interested in the experimental gene therapy after he had begun to rebel against the restrictive nonprotein diet and the 50 pill-a-day regimen that mitigated his symptoms. He faced a life of increasingly larger doses of medication.

''He was a a rebellious teenager who thought he could manage his own illness,'' his father said.

Jesse was especially interested in the gene trial since it promised dramatic improvement.

Jesse was also interested because the particular phase of the trial he was in might benefit newborns who get the worst form of the disease that kills in the first year.

Paul Gelsinger and Jesse, who at 18 was the actual person giving consent for the trial, were told the largest risks from the trial would come from possible hepatitis and blood clots. The cause of death has not been determined, Mr. Gelsinger said, ''but it's obvious it had to have been the procedure itself.''

Mr. Gelsinger does not have hard feelings toward the doctors in the trial. ''The doctors are as devastated as I am. It was because of these men that I had my son for 18 years.''

Jesse died on Sept. 17, when artificial life support was discontinued, but his vital signs began to fail the second day after the introduction of the modified gene on Monday, Sept. 13.