by The lone volunteer in a gene-editing study targeting a rare form of Duchenne muscular dystrophy likely died after a reaction to the virus the therapy delivered to his body, researchers concluded in an early study.
Terry Horgan, 27, of Montour Falls, New York, died last year during one of the first trials of a gene-editing treatment designed for one person. Some scientists questioned whether the gene-editing tool CRISPR played a role in his death. The tool has transformed genetic research, spurred the development of dozens of experimental drugs, and its inventors won the 2020 Nobel Prize.
But researchers said the virus — a virus that used to get treatment into the body because it usually doesn’t make people sick — combined with his condition caused the problems that ultimately killed him.
Horgan appears to have had a more severe immune reaction “than others who received similar or slightly higher doses of the virus,” the authors wrote in the study, which has not yet been peer-reviewed.
Horgan participated in an early stage safety study approved by the Food and Drug Administration. It was sponsored by Cure Rare Disease, a Connecticut-based nonprofit founded by his brother Rich, to try and save him from the muscle-wasting disease caused by a mutation in the gene needed to make a protein called dystrophin.
In a statement, Rich Horgan thanked the research team led by the University of Massachusetts Chan Medical School and Yale University for a “thorough, comprehensive” study that provided valuable insights. He added: “Personally, this study is another important step towards honoring Terry’s legacy and his commitment, as well as that of our entire family, to the rare disease community.”
The therapy Horgan received focused on using CRISPR to increase a form of the dystrophin protein. The trial began by suppressing Horgan’s immune system to prepare his body for the therapy, which was administered by IV with “a high dose” of what’s known as an adeno-associated viral vector, or AAV, according to Cure Rare Disease.
But Horgan soon ran into trouble, going into cardiac arrest six days after treatment and dying two days later from organ failure and brain damage. Due to the timing of the symptoms and the fact that researchers could find little of a gene-editing enzyme in his body, they concluded that the therapy had not yet been activated.
This isn’t the first time viral vectors have been implicated in the death of a gene therapy trial. In a major setback for the field, 18-year-old Jesse Gelsinger died in 1999 during a trial aimed at combating his rare metabolic disease. Scientists later found out that his immune system overreacted to the virus used to carry the treatment. The virus used in Horgan’s trial is considered safer, but it’s not without its problems.
“People have tried to create safer vectors…but they remain a challenge,” said Arthur Caplan, a medical ethicist at New York University who was not involved in the study but has closely followed the case. “We don’t really understand why some people get into trouble and others don’t. We don’t know if it’s their underlying disease, a comorbidity or a foreign immunology.’
Rich Horgan said they plan to submit the study to a peer-reviewed journal. Meanwhile, Cure Rare Disease said it will use alternative viruses for the other treatments it is trying to develop.
Dr. Terence Flotte, dean of UMass Medical School and senior author of the study, said he hopes it leads to “further research into identifying subgroups of patients who may be predisposed to these types of severe, unexpected reactions.”
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