Human Gene Therapy : Progress, The Gelsinger Case

by Food and Drug Administration (FDA)

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The Gelsinger Case

When Orkin and Motulsky reported on the technical limitations of gene transfer techniques five years ago, they virtually predicted problems in the clinic. During that same December meeting at which Orkin and Motulsky made their disheartening report, the RAC approved the University of Pennsylvania gene therapy trial for ornithine transcarboxylase deficiency (OTCD). FDA, too, allowed the study to proceed.

The treatment idea was fairly straightforward. OTCD occurs when a baby inherits a broken gene that prevents the liver from making an enzyme needed to break down ammonia. With the OTCD gene isolated, the University of Pennsylvania researchers packaged it in a replication-defective adenovirus. To reach the target cells in the liver, the Philadelphia scientists wanted to inject the adenovirus directly into the hepatic artery that leads to that organ. Some members of the NIH RAC objected, fearing that direct delivery to the liver was dangerous. Nonetheless, after a vigorous public discussion with the University of Pennsylvania researchers, the RAC voted for approval of the study.

At age 18, Jesse Gelsinger was in good health, but was not truly a healthy teenager. He had a rare form of OTCD that appeared not to be linked to his parents, but the genetic defect arose spontaneously in his body after birth. During his youth, he had many episodes of hospitalization, including an incident just a year before the OTCD trial in which he nearly died from a coma induced by liver failure. But a strict diet that allowed only a few grams of protein per day and a pile of pills controlled his disease to the point where he appeared to be a normally active teenager. With the encouragement of his father, Paul Gelsinger, Jesse volunteered for the study, and when he was initially evaluated, his medical condition qualified him to participate.

Gelsinger received the experimental treatment in September 1999. Four days later, he was dead. No one is really sure exactly why the gene therapy treatment caused his death, but it appears that his immune system launched a raging attack on the adenovirus carrier. Then an overwhelming cascade of organ failures occurred, starting with jaundice, and progressing to a blood-clotting disorder, kidney failure, lung failure, and ultimately brain death.

In its investigation, FDA found a series of serious deficiencies in the way that the University of Pennsylvania conducted the OTCD gene therapy trial, some more serious than others. For example, researchers entered Gelsinger into the trial as a substitute for another volunteer who dropped out, but Gelsinger's high ammonia levels at the time of the treatment should have excluded him from the study. Moreover, the university failed to immediately report that two patients had experienced serious side effects from the gene therapy, as required in the study design, and the deaths of monkeys given a similar treatment were never included in the informed consent discussion.

FDA's discussions with the university remain ongoing.

Signs of Progress

Not all the news about gene therapy is bad. It's true that dramatic cures have not been seen to date, but there are tantalizing signs that important advances may be just around the corner.

Ashanthi DeSilva, the girl who received the first credible gene therapy, continues to do well a decade later. She suffered a type of inherited immune disorder called Severe Combined Immune Deficiency, or SCID (pronounced skid), that left her susceptible to every passing microorganism. Without gene therapy, DeSilva would be living like David, the Boy in the Bubble, who had a similar disorder. Instead, the NIH researchers inserted a normal copy of the broken gene into some of her white blood cells, healing them, helping them function normally to restore her immune system. Cynthia Cutshall, the second child to receive gene therapy for the same disorder as DeSilva, also continues to do well.

Scientists, however, have discounted the benefit of the first gene therapies because the girls began receiving a new drug treatment that replaces the missing enzyme just before receiving the genetic therapy. And they continue to receive the drug after the genetic treatment, though gene therapy pioneer Anderson argues that since the drug dose has remained the same while their bodies have grown substantially over the decade, it makes a negligible contribution to their well being.

In April, French scientists reported convincing evidence that they successfully treated a different form of SCID (X-linked severe combined immune deficiency, the type suffered by the boy in the bubble) with gene therapy. Four of the first five babies treated by Alain Fischer, M.D., of the Necker children's hospital in Paris have had "a complete or near complete recovery" of their immune systems after the treatment.

Meanwhile, researchers at Children's Hospital of Philadelphia, Stanford University and Avigen, Inc., a biotech company in Alameda, Calif., have reported promising results in hemophilia B patients. The team packaged a gene for Factor IX, a blood clotting protein, in a defective adeno-associated virus (AAV). They then used the AAV to insert the gene into patients who suffered abnormal blood clotting because they lack Factor IX. Normally, these hemophilia patients needed to inject Factor IX to prevent uncontrolled bleeding. In June, the researchers reported treating six patients with the Factor IX gene therapy. Even though the dose of the gene therapy was so low that no one expected it to help, it reduced the number of injections of Factor IX that these patients used on an ad hoc basis.

"The hemophilia studies are looking promising," says FDA's Noguchi, "but will need further study to know whether it is an effective product."

These two studies suggest the power of genetic treatments.

"We do seem to have turned the corner," says Anderson, "and there are a number of clinical trials that are starting to show success."

Even as FDA increases its scrutiny of the field to ensure patient safety, there is a sense of advancement. "There is good progress being made," Noguchi says. "FDA thinks that gene therapy will work, but we don't know for which disease. The recent events in France show that if you have the right disease, and can insert the right gene, you can obtain good results."

About the Author

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