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Death in CRISPR gene therapy study sparks search for answers

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The only volunteer in a unique study involving a gene-editing technique has died, and those behind the trial are now trying to figure out what killed him.

Terry Horgan, a 27-year-old man with Duchenne muscular dystrophy, died last month, according to Cure Rare Disease, a Connecticut-based nonprofit founded by his brother, Rich, to try to save him from the disease. fatal illness.

Although little is known about how he died, his death occurred during one of the first studies to test a gene-editing treatment designed for a single person. This raises questions about the holistic perspective of these therapies, which have given hope to many families facing rare and devastating diseases.

“This whole idea that we can tailor gene 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 at the limit of experimentation.”

The early-stage safety study was sponsored by the nonprofit, led by Dr. Brenda Wong of the University of Massachusetts Chan School of Medicine and approved by the Food and Drug Administration. The hope was to use a gene-editing tool called CRISPR to treat Horgan’s particular form of Duchenne muscular dystrophy. This rare genetic muscle wasting disease is caused by a mutation in the gene needed to produce a protein called dystrophin. Most people with Duchenne die of lung or heart problems caused by it.

At this point, it’s unclear whether Horgan received the treatment and whether CRISPR, other aspects of the study, or the disease itself contributed to his death. Deaths are not unheard of in clinical trials, which test experimental treatments and sometimes involve very sick people.

But trials involving CRISPR are relatively new. And Fyodor Urnov, a CRISPR expert at the Innovative Genomics Institute at the University of California, Berkeley, said any death during a gene therapy trial is an opportunity for the field to take stock.

“The first step is to mourn the passing of a brave human soul who agreed to participate in an experiment on a human being,” Urnov said. “But then, as much as we can, we have to learn as much as we can to chart a path forward.”

FEW ANSWERS YET

A statement from Cure Rare Disease said several teams across the country are studying the details of the trial and its results, and the company intends to share the results with the scientific community.

“It will likely take 3-4 months to come to a full conclusion,” spokesman Scott Bauman said. “At this stage of the game, to say anything is pure speculation.”

The company, which is also working on 18 other therapies, said in its statement that the teams’ work is essential not only to shed light on the study’s results, but also “on the challenges of gene therapy more broadly.” “. During this time, he said, “We will continue to work with our researchers, collaborators and partners to develop therapies for neuromuscular diseases in our pipeline.”

Bauman said the company has filed a death report with the FDA, as required. The FDA declined to release or confirm the report.

Sarah Willey, spokeswoman for Chan Medical School, said scientists there had provided data to the company for the report. She later emailed to say no one would comment further; out of respect for the wishes of the family, all information would come from Cure Rare Disease. Monkol Lek, a Yale genetics expert who collaborated on the effort, did not respond to a request for comment. Yale spokeswoman Bess Connolly asked a reporter for background to the story, but did not respond to a follow-up email or phone call.

A crucial question is whether CRISPR played a role in Horgan’s death.

The chemical tool can be used to “edit” genes by making cuts or substitutions in the DNA. The tool has transformed genetic research and sparked the development of dozens of experimental therapies. The tool’s inventors won a Nobel Prize in 2020.

In this case, scientists used a modified form of CRISPR to increase the activity of a gene. CRISPR therapy is inserted directly into the body and delivered to cells with 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 can be issues with … viral vectors” that deliver therapy into the body, he said. “Red flags are flying here. We have to make sure they are dealt with very, very quickly.

Safety issues have already arisen in gene therapy studies. Late last year, Pfizer reported the death of a patient in its preliminary trial for a different gene therapy for Duchenne muscular dystrophy. And in a major setback for the field of gene therapy, 18-year-old Jesse Gelsinger died in 1999 during a study that involved placing healthy genes in his liver to fight a rare metabolic disease. Scientists later learned that his immune system had overreacted to the virus used to deliver the therapy. Many recent studies, including the Cure Rare Disease trial, use a different virus considered safer.

Another difference? The recent lawsuit involved only one person — a type of lawsuit that Caplan is skeptical of.

Horgan’s recent death, he said, “may make us think about whether we really like studies that only involve one person, and do we want to say, ‘No, ethically you have to at least have a trial where you are online up to 5, 10, 20 people (and) you learn from the data. ”

A “MEDICAL PIONEER”

On the company’s website, Horgan was described as a “medical pioneer” who “will be remembered as a hero”.

In 2020, the Montour Falls, New York resident blogged that he was diagnosed with Duchenne when he was 3 years old. As a child, he said, he loved computers – once he built his own – and played ball in the driveway with his family when he could still walk. Later in life he used a motorized wheelchair. He studied information science at Cornell University and later worked at the school in the information science department.

“As I grew older and began to understand what it was like to have DMD, my fears about this disease began to grow as it began to manifest itself,” Horgan wrote. “There weren’t many, if any, trials available to me over the years” – until this one brought the prospect of personalized medicine.

Horgan was enrolled in the study on August 31. The plan was to suppress his immune system to prepare his body for a unique gene-editing therapy given intravenously at UMass medical school, followed by hospital monitoring. The company explained that the therapy is designed to increase the level of an alternative form of the protein dystrophin using CRISPR, with the aim of stabilizing or potentially reversing the progression of symptoms.

Urnov, scientific director of technology and translation at Berkeley’s Genomics Institute, said no other trial targets this disease using this type of virus to deliver this particular payload with its modified form of CRISPR.

Some other gene therapy trials — such as those targeting the blood disorders of sickle cell anemia and beta-thalassemia — involve taking stem cells from a person’s blood, using CRISPR in the lab, and then putting the altered cells back in. in the person. The first time CRISPR was used to edit genes in the body was to treat a blindness-causing mutation.

Given the “exceptional distinction” of the Cure Rare Disease approach, Urnov said he doesn’t think Horgan’s death will have a major impact on things like the use of gene therapy to cure diseases of the blood. But he said figuring out the exact cause would help inform scientists across the field.

“History teaches us that in the case of such deaths – which have been rare – that a deep dive into what happened was essential for the field to move forward.”

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The Associated Press Health and Science Department is supported by the Howard Hughes Medical Institute Department of Science Education. The AP is solely responsible for all content.