Last October, a 27-year-old man with Duchenne muscular dystrophy died after receiving a CRISPR-based treatment custom built to treat his particular genetic mutation.
Results of a detailed investigation released on Wednesday suggest that the patient, Terry Horgan, likely died of a previously undocumented adverse effect of the virus used to deliver the CRISPR machinery to his cells.
These viruses, known as adeno-associated viruses, or AAVs, are used in several approved drugs and hundreds of clinical trials to deliver genes into patients, because they are generally benign. But at high doses they can cause side effects and, occasionally, deaths through one of several mechanisms, such as directly injuring the liver or triggering a type of immune response known as complement activation.
Terry, whose family requested reporters refer to by his first name, appeared to mount a significant innate immune response against the virus that eventually triggered acute respiratory distress syndrome, or ARDS, where fluid builds up in the lungs. It is the same syndrome that affects many severe Covid patients when their immune system goes haywire.
Researchers and the family knew high-dose AAV carried significant risks, including death, in an older patient with Duchenne, a degenerative disease that takes many patients before age 30. But ARDS had not previously been documented in the immediate days after receiving AAV. And the effects appeared to be exacerbated by the fact that, per the autopsy, Terry’s heart had suffered greater damage from Duchenne prior to therapy than doctors could observe on a standard measure of cardiac function.
“I don’t think it was foreseeable based on previous experience even with high dose AAV,” said Kathy High, a longtime gene therapy researcher who was not involved in the work.
The paper, published Wednesday in the New England Journal of Medicine, offers an unusually detailed look into a death in a gene therapy trial. Companies have not routinely published the findings from gene therapy deaths, even as such cases have increased with the rise in clinical trials.
“I think it’s a service to the field to publish this case in detail,” said High.
Three years after the first of ultimately four boys died in a trial for a rare muscle disease therapy, Astellas has not published details. And Pfizer has not published details on the death, in 2021, of a 16-year-old Duchenne patient. Both companies have presented some findings at academic meetings.
The authors on the NEJM paper, led by Terry Flotte, provost and executive deputy chancellor of UMass Chan Medical School, where Terry was treated, suggested this same sequence may have also been what killed the boy in the Pfizer trial.
Terry’s treatment was developed by Cure Rare Disease, a nonprofit his brother, Rich Horgan, founded.
The nonprofit is now working with academics and patient families to develop treatments for other diseases caused by ultra-rare mutations, including other mutations that cause Duchenne. Its gene therapy programs now rely on a different virus that can potentially be given at lower doses.
“We are grateful to the multi-institutional scientific team who led this study to gain the best learnings we could from this devastating outcome,” Rich Horgan said in a statement. “By contributing knowledge where very little currently exists, we hope that this may help other patients to receive safe, efficacious treatment someday. Transparency in clinical trials, no matter the outcome, paves the way for critical knowledge to be learned and shared across teams, enabling medical innovation.
“As we approach the one-year anniversary of Terry’s passing, we remember his courage and motivation to move science forward for other rare and ultra-rare disease patients,” he added. “This steadfast commitment continues in our work at Cure Rare Disease today.”
Experts cautioned that it was difficult to draw broad conclusions from a single patient. But the paper underscored concerns about giving high doses of AAV, particularly to older patients. Although newer, more targeted viruses are being developed — like the one Cure Rare Disease is now relying on — these high doses are often needed today to reach a requisite number of muscle cells. Give too low a dose and you expose a patient to risk without any potential for benefit.
So far, most of the patients to receive high-dose AAV have been children. The paper hypothesized that in a patient like Terry, who had already lost significant muscle mass, a similar dose might pose larger safety risks because each remaining muscle cell is getting more virus.
The authors’ conclusion also notably mirrors that in the death of Jesse Gelsinger, an 18-year-old who died in a gene therapy trial in 1999 after receiving a different, more immune-stimulating virus. Gelsinger’s death shut down the field for years, as researchers developed newer and safer viruses — namely, AAV.
Jim Wilson, the University of Pennsylvania professor who designed the therapy Gelsinger received and investigated his death, commended Flotte and the team on the investigation. But he said in an email that the case for ARDS was actually less strong in this case and suggested an alternative explanation: The virus could have caused direct damage by going at high levels into an already weakened heart. The ARDS would have been secondary to the heart damage.
That sequence of events would also be new and not previously described in the literature on AAV.