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Decades after a tragic failure, gene therapy successfully treats a rare liver disease

Twenty-two years ago, one of scientists’ first attempts at gene therapy ended in tragedy when a young man died. The story of Jesse Gelsinger, who had a rare liver disorder, became a textbook example of irresponsible medical research. For years, the case hobbled efforts to treat diseases by adding new DNA to a sick person’s cells. Now, a fresh effort to cure Gelsinger’s disease is bearing fruit, in the latest sign of the field’s resurgence.

The small, ongoing trial for ornithine transcarbamylase (OTC) deficiency, sponsored by the company Ultragenyx, hasn’t helped everyone with the inherited disease, which causes dangerously high ammonia levels in the blood and affects an estimated one in 50,000 people. Still, there have been no serious safety problems. Many of the 11 participants have been able to relax dietary restrictions and drop medications, including three who no longer need those measures at all, researchers reported last week at the virtual meeting of the American Society of Gene & Cell Therapy (ASGCT).

“It’s very heartening that this went well and there were no untoward effects and partial efficacy,” says geneticist Ada Hamosh of Johns Hopkins University, who treats patients with OTC deficiency. “After really rocky beginnings, people took the time to do the biology” and craft a better therapy.

Jesse’s father, Paul Gelsinger, who is not a scientist but has followed the trial, agrees. “I think it’s great that Ultragenyx had the courage to take on OTC. … I also think it’s wonderful that they have achieved efficacy, even limited,” says Gelsinger, whose son would have been 40 years old this year.

People born with OTC deficiency lack an enzyme needed to turn excess nitrogen from protein into urea. This leads to the buildup of ammonia, which can cause coma, brain damage, and death. Because the OTC gene is on the X chromosome, the disease is often fatal in infant boys. But girls, who have a second, working copy of the gene, and boys with mutations that give them a partially functioning OTC enzyme can reduce ammonia overload with a low-protein diet and drugs.

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