In October 2022, the only world's muscular volunteer (Duchenne muscular dystrophy, DMD), involved in CRISPR gene editing therapy, died in the course of treatment. The 27-year-old patient, named Terry Horgan, had a DMD with a rare genetic mutation and would cause his death before age 30. Terry formed the Cure Rare Disease (CRD) team for his own brother, Richard Horgan, and spent millions of dollars on his specially developed and designed CRISPR therapy. Terry was the only trial participant in the therapy.
CRD: Founded, eager to save my brother, dedicated to gene editing therapy
The Duchenne muscular dystrophy affected by Terry is a rare inherited disorder of muscular atrophy caused by mutations in the gene encoding for dystrophin production. It affects all muscle types, causing loss of mobility, eventually leading to respiratory and heart failure. Patients with DMD usually die before the age of 30 years. One person in every 3,500 men born is affected by the disease, which is extremely rare in women.
As Terry's DMD has the rarest mutation, and recent DMD gene therapy usually targets children, Terry cannot benefit from recent trials of DMD gene therapy. In 2017, Richard, who is still studying at Harvard Business School, founded CRD, a nonprofit organization in Boston, aiming to customize personal gene therapy for his own brother, Terry, and treat Terry's DMD. The CRD research team consists of professionals from Yale University, the University of Massachusetts Chan School of Medicine, and the Charles River Laboratory (Figure 2). The research team developed and tested a unique DMD treatment for Terry's genetic mutation, and named it CRD-TMH-001.
On August 9,2022, the CRD announced that the US Food and Drug Administration (Food and Drug Administration, FDA) had approved the CRD-TMH-001 for clinical trials, and that the administration of the drug was conducted at the University of Massachusetts School of Medicine. The therapy is a one-time administration, and Terry will receive intravenous medication and be monitored in the hospital for several days to ensure that there are no uncontrolled adverse effects. Following Terry discharge, the CRD will follow the patients for 15 years following the FDA guidelines to track disease progression. Currently, the therapy is only used to treat Terry Horgan, and to protect patient privacy, the CRD will not comment on it after the trial begins.
CRD-TMH-001 is used to treat Duchenne muscular dystrophy by using CRISPR technology to upregulate another form of dystrophin (isotype), acting on muscle promoter and exon 1 mutations on protein genes, thus stabilizing or may reverse the symptomatic progression of Duchenne muscular dystrophy. This is the first human trial of CRISPR therapy designed to change the way the body responds to the existing genetic code, rather than changing the gene itself. This is also the first trial of personalized CRISPR therapy and the first trial of gene editing techniques for DMD.
Terry's death has once again raised questions about the safety of CRISPR
So far, the cause of death for Terry Horgan has not been announced. Reporting of the incident has been provided to the FDA as required by the clinical trial. Several US research teams are reviewing the possible cause of Terry's death and have said: " This is a complex task that can take up to four months.”
The CRD-TMH-001 is funded by the Horgan Family Fund, which said in a statement: " Terry was diagnosed with DMD when he was three, has loved computers since childhood, and once built his own computers. When he could still walk, he played hide-and-seek in the driveway with his family. Later in his life, Terry began using an electric wheelchair, studying information science at Cornell University, and continuing to work in the Department of Information Science. Terry's death is heartbreaking, and he will be remembered as a hero.”
Gene therapy has raised hope for many families facing rare and incurable diseases, but Terry's death has raised questions about the overall promise of gene-editing therapy. CRISPR has been critically mixed since its debut in 2012. Some scientists believe CRISPR has the potential to change medicine by helping treat and prevent serious diseases such as cancer and neurodegenerative diseases, could one day help cure people with cancer or HIV and allow doctors to repair defective DNA. The inventor of the tool was awarded the Nobel Prize in 2020. While bringing hope, the CRISPR is not perfect. Some scientists believe that CRISPR is at risk of mischanging DNA or RNA in regions outside the target site, which can lead to adverse side effects. For example, an unexpected modification of tumor suppressor genes may lead to cancer.
Safety issues in gene-editing technology research are not alone. Jesse Gelsinger died in 1999 at the age of 18 in a study involving inserting healthy genes into his liver to fight a rare metabolic disease. In 2019, He modified the DNA before the twin girls, Lulu and Nana, were born to make them resistant to HIV. More than 100 Chinese scientists have slammed He's work: " Direct human experiments can only be described as madness. The Pandora's box had been opened. We may still have a glimmer of closing it before it is too late."In 2021, Pfizer reported that a patient had died in an early trial of DMD gene therapy. The latest deaths related to CRISPR technology could undermine public trust in its use in an ethical, safe manner.
Dr. Arthur Caplan, a medical ethicist at New York University, said: " We know that CRISPR may miss its goal. We know that CRISPR can be partially effective, and we also know that viral vectors delivering therapy to in vivo can be problematic. The CRD-TMH-001 was performed only in one patient, and the sample size was too small. Terry's death may make us think about whether we really like research on just one person? Ethically, you have to have at least one trial, and we need to learn from the data.”
Meanwhile, CRD, which supports the development of gene-editing therapies for 18 other rare diseases, said in a statement: " Terry is a medical pioneer whose courage and firm determination have paved the way for funding for patients with rare and ultra-rare diseases and to develop new therapies. The work of the CRD team is critical not only to elucidating the results, but also to extensively address the challenges of gene therapy ". Fyodor Urnov, an CRISPR expert at the Institute of Innovative Genomics at the University of California, Berkeley, said: " Any death during a gene therapy trial is an opportunity to evaluate the field. Terry is a brave trial participant, and within our capacity, we must learn as much as possible from his death to open a way forward.”
