Terry Horgan, the patient who was undergoing gene editing treatment being conducted by Cure Rare Disease, a Connecticut-based nonprofit founded by his brother, Rich, to try and save him from the fatal condition, died during the landmark Crispr study.
The only participant in a new study employing a gene-editing technique has passed away, and the trial’s organisers are now attempting to determine what caused his death.
Terry Horgan, a 27-year-old who had Duchenne muscular dystrophy, died last month, according to Cure Rare Disease, a Connecticut-based nonprofit founded by his brother, Rich, to try and save him from the fatal condition.
Little is known about how he passed away, although it happened during one of the initial trials of a gene editing treatment made just for him. It’s generating concerns about the potential of such treatments generally, which have raised hopes among many families dealing with rare and fatal diseases.
“This whole notion that we can do designer genetic therapies is, I would say, uncertain,” said Arthur Caplan, a medical ethicist at New York University who is not involved in the study. “We are out on the far edge of experimentation.”
The nonprofit group funded the early-stage safety study, which was authorised by the Food and Drug Administration and headed by Dr. Brenda Wong of the University of Massachusetts Chan Medical School. The goal was to treat Horgan’s particular type of Duchenne muscular dystrophy using the gene-editing technology CRISPR. A mutation in the gene required to create the protein known as dystrophin is the cause of the rare, hereditary disorder that causes muscular atrophy. The majority of Duchenne patients pass away due to heart or lung problems.
It is now unknown whether Horgan received the medicine and whether CRISPR, other research components, or the disease itself played a role in his death. Clinical trials, which test new medicines on sometimes-very-ill patients, are not without deaths.
CRISPR experiments, however, are a recent development. Any death during a gene therapy study, according to Fyodor Urnov, a CRISPR specialist at the Innovative Genomics Institute at the University of California, Berkeley, is a chance for the field to make amends.
“Step one is to grieve for the passing of a brave human soul who agreed to be basically a participant in an experiment on a human being,” Urnov said. “But then, to the extent that we can, we must learn as much as we can to carve out a path forward.”
Few Answers Yet
Multiple teams around the country are investigating the details of the experiment and its results, according to a statement from Cure Rare Disease. The company plans to share its findings with the scientific community.
“It will probably be 3-4 months to come up with a full conclusion,” said spokesman Scott Bauman. “At this stage of the game, saying anything is pure speculation.”
The teams’ work is crucial, according to the company, which is also working on 18 other therapeutics, to provide light not just on the results of the trial but also “on the challenges of gene therapy broadly.” Meanwhile, it said, “we will continue to work with our researchers, collaborators, and partners to develop therapies for the neuromuscular diseases in our pipeline.”
According to Bauman, the business has properly filed a death report to the FDA. The FDA declined to make the study public or confirm it.
Scientists at Chan Medical School, according to spokesperson Sarah Willey, gave information to the company for the report. Later, she sent an email to indicate that no one will comment further and that all information would come from Cure Rare Disease out of respect for the family’s wishes. In response to a request for comment, Monkol Lek, a Yale genetics expert who has been working on the project, remained silent. Bess Connolly, a spokesperson for Yale, requested a reporter for background information on the story but didn’t reply to a subsequent email or phone call.
Whether CRISPR was involved in Horgan’s death is a crucial question.
The chemical tool may “edit” genes by modifying DNA through cuts or substitutions. The instrument has revolutionised genetic research and prompted the creation of numerous experimental treatments. The tool’s creators received a Nobel Prize in 2020.
In this instance, researchers changed the CRISPR system to boost a gene’s activity. The CRISPR treatment is administered intravenously to cells carrying a virus.
But CRISPR is not perfect.
“We know that CRISPR can miss its target. We know that CRISPR can be partially effective. And we also know that there may be issues with … viral vectors” that deliver the therapy into the body, Caplan said. “Red flags are flying here. We’ve got to make sure that they get addressed very, very quickly.”
Studies on gene therapy have occasionally encountered safety concerns. Pfizer reported the death of a patient late last year in an early-stage trial for a separate gene therapy for Duchenne muscular dystrophy. The 18-year-old Jesse Gelsinger passed away in 1999 while participating in a trial that involved inserting healthy genes into his liver to treat a rare metabolic condition, which was a significant setback for the area of gene therapy at the time. Scientists eventually discovered that the virus employed to deliver the medication caused his immune system to overreact. A different virus that is thought to be safer is used in numerous recent experiments, including the Cure Rare Disease study.
The recent trial only featured one person, which is a kind of trial Caplan is dubious of.
Horgan’s recent death, he said, “may make us think whether we really do like studies that are just on one person, and do we want to say: ‘No, ethically, you’ve got to at least have a trial where you line up 5, 10, 20 people (and) you learn from the data.’ ”
A ‘Medical Pioneer’
Horgan was referred to as a “medical pioneer” who “will be remembered as a hero” on the company’ website.
The Montour Falls, New York resident revealed in 2020 that he received his Duchenne diagnosis when he was 3 years old. He recalled that when he was younger, he enjoyed playing catch with his family in the driveway and had even built his own computer. He later used a wheel chair. He earned a degree in information science from Cornell University and afterwards worked there in the information science department.
“As I grew up and began to understand what it meant to have DMD, my fears about this disease began to grow as it began to manifest,” Horgan wrote. “There weren’t many, or any, trials available to me through the years” — until this one brought the prospect of a customized drug.
On August 31, Horgan joined the study. His immune system was to be suppressed in order to prepare his body for a single, IV-delivered gene-editing therapy at the UMass medical school, followed by hospital monitoring. The therapy, according to the company, aims to stabilise or maybe stop the progression of symptoms by utilising CRISPR to boost levels of a different type of the dystrophin protein.
According to Urnov, the scientific director for technology and translation at the Berkeley Genome Institute, no previous experiment used this type of virus to deliver this specific payload with its modified form of CRISPR to target this condition.
In certain other gene therapy trials, such as those for sickle cell disease and beta thalassemia, stem cells from a patient’s blood are taken, changed in the lab using CRISPR, and then returned to the patient. The first time CRISPR was used to modify a gene within the body was to correct a mutation that causes blindness.
The “exceptional distinctness” of the Cure Rare Disease strategy, according to Urnov, means that he doesn’t believe Horgan’s death will significantly affect ideas like using gene therapy to treat blood diseases. However, he asserted that identifying the exact cause will help scientists across the board.
“History teaches us that in the case of such fatalities – which have been rare – that a deep dive into what happened was critical for the field to move forward.”