May 26, 2024

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A DMD patient died after receiving CRISPR gene-editing therapy

A DMD patient died after receiving CRISPR gene-editing therapy: Autopsy results show, or from an immune response to AAV vector.

A DMD patient died after receiving CRISPR gene-editing therapy: Autopsy results show, or from an immune response to AAV vector.

The emergence and application of CRISPR gene editing technology has brought unprecedented hope for the treatment of genetic diseases.

In recent years, we have also seen the clinical progress of CRISPR gene editing in rare genetic diseases, cancer, and cardiovascular diseases. Families with rare and devastating illnesses find hope.

In October 2022, a 27-year-old Duchenne muscular dystrophy (DMD) patient named Terry Horgan tragically passed away after receiving CRISPR gene-editing therapy delivered by an adeno-associated virus type 9 (AAV9) vector.

Its death has raised concerns and questions about the prospects for CRISPR gene-editing therapies.


On May 16, 2023, researchers from the American Muscular Dystrophy Society, the University of Massachusetts Medical School, and Yale University published on the preprint platform medRxiv titled: Unexpected Death of a Duchenne Muscular Dystrophy Patient in an N-of-1 Research paper on Trial of rAAV9-delivered CRISPR-transactivator .

A DMD patient died after receiving CRISPR gene-editing therapy: Autopsy results show, or from an immune response to AAV vector.

The research team conducted an in-depth analysis of the cause of Terry Horgan ‘s death.

The autopsy results showed that his lungs were damaged, which may be caused by a strong immune response to high doses of adeno-associated viral vector (AAV) vectors .

The patient received a custom-made CRISPR-dCas9-VP64 gene-editing therapy designed to upregulate dystrophin expression to treat Duchenne muscular dystrophy (DMD) .

After receiving treatment and developing signs of mild cardiac dysfunction and pericardial effusion, the patient developed acute decompensated heart failure and sustained cardiac arrest 6 days after dosing, and died 2 days later.

Autopsy revealed severe acute respiratory distress syndrome with diffuse alveolar damage and minimal expression of the transgene in the liver. He had no evidence of AAV9 antibodies nor effector T cell responses.

These findings suggest that innate immune signaling and capillary leak are also a form of toxicity in older DMD cases receiving high-dose AAV gene therapy.

The patient was previously treated at a dose of 1 × 10E14 vg/kg, which was similar to the dose tested in other clinical trials, but resulted in a higher viral vector genome load in this patient, which the research team attributes to the patient’s lower lean muscle mass. Low.

The study also found that this patient developed a more severe innate immune response than those with DMD who received similar or higher AAV doses in the mini-dystrophin gene therapy clinical trial.

Based on these findings, the research team believes that more data are needed on features that may predispose people to severe innate immune responses when conducting AV gene therapy, and that dosing will remain a challenge for custom-designed AAV gene therapies.

Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-chromosomal recessive genetic disorder and therefore primarily affects boys.

According to statistics, about 1 in every 3,500 newborn boys in the world suffers from this disease.

The onset of the disease usually begins at the age of 3-5 years, with the earliest signs of progressive muscle weakness in the legs, leading to difficulty walking.

Loss of the ability to walk usually occurs by age 12, and heart and respiratory weakness begin in adolescence and lead to serious complications, usually death from respiratory and heart failure by the age of 20-30.

As a single-gene disease, Duchenne muscular dystrophy (DMD) is caused by mutations in the Dystrophin gene encoding dystrophin on the X chromosome.

The mutated Dystrophin gene cannot produce sufficient or functional dystrophin, and the patient’s Muscle tissue is gradually replaced by fatty and fibrotic tissue.

Custom CRISPR Gene Editing Therapies

The protagonist of this article, Terry Horgan , was diagnosed with Duchenne muscular dystrophy ( DMD) when he was 3 years old . Rare disease patients like Terry.

In 2019, Richard teamed up with scientists from the University of Massachusetts and Yale University to develop a tailor-made CRISPR gene editing therapy for his younger brother Terry.

In August 2022, the FDA approved the clinical trial application for this CRISPR gene editing therapy, called CRD-TMH-001, for the treatment of Terry’s Duchenne muscular dystrophy (DMD), which is the first personalized CRISPR gene editing therapy , and is also the first clinically approved CRISPR gene editing therapy for the treatment of DMD.

The Dystrophin gene is very large, with as many as 79 exons, and mutations in different exons may lead to DMD. Because the gene is so large, direct delivery of the correctly coded Dystrophin gene into cells was not feasible.

For Terry, he is a deletion mutation of exon 1 of the Dystrophin gene, and the CRD-TMH-001 therapy hopes to promote the expression of the isoform of the dystrophin protein encoded by the Dystrophin gene through CRISPR technology , to stabilize or reverse the progression of DMD.

Patient dies

Terry once said that he liked computers since he was a child, and tried to assemble computers by himself when he was still able to walk. After that, he studied information science at Cornell University and stayed at Cornell University’s Department of Information Science.

As the disease progressed and he had to rely on an electric wheelchair for mobility, he said his fear of the disease also increased. But he has not participated in any clinical trials of treatment until this time when the gene editing therapy was customized for him.

On August 31, 2022 , Terry started a CRISPR gene editing clinical trial, funded by Cure Rare Disease and led by Dr. Brenda Wong from the University of Massachusetts .

However, on October 14, 2022, Cure Rare Disease announced Terry’s tragic death . The announcement reads: Terry Horgan , the younger brother of Cure Rare Disease founder and CEO Richard Horgan , unfortunately passed away.

He participated in a clinical trial of a new CRISPR gene editing therapy CRD-TMH-001. The cause of his death is still unclear. The loss of Terry is heartbreaking, but he will also be remembered as a hero , a medical pioneer whose courage and unwavering determination paved the way for greater attention, funding and development of new treatments for rare diseases.

Cure Rare Disease has reported this situation to the FDA, and combined multiple teams to study the details and results of this clinical trial to find the real cause of Terry’s death and whether it is related to CRISPR or the treatment itself.

Moving forward through tragedy

In fact, death events in clinical trials are not uncommon, because the clinical trials themselves are experimental and exploratory, and many people participating in the clinical trials are already seriously ill.

In 1999, at the early stage of gene therapy research, an 18-year-old boy, Jesse Gelsinger , died after receiving adenovirus gene therapy for ornithine transcarbamylase deficiency (OTC) , becoming the world’s first A man who died from gene therapy. Follow-up studies showed that the adenoviral vector caused him to develop a severe immune response and multiple organ failure.

His tragedy led the FDA to strictly review gene therapy clinical trials.

At that time, the gene therapy star carrier adenovirus gradually declined, and the entire gene therapy field began to be silent for 20 years.

After this tragedy, Professor Jim Wilson began to work on finding a safer gene therapy vector, and discovered and promoted the adeno-associated virus (AAV) vector. The clinical trial Terry accepted also used the adeno-associated virus (AAV) vector.

In 2017 and 2019, the FDA successively approved two AAV gene therapies for marketing, which revived the gene therapy field that had been silent for 20 years. Today, hundreds of AAV gene therapy clinical trials are underway all over the world.

As clinical trials of AAV gene therapy progress, related patient deaths also begin to occur, for example, in late 2021, a patient death occurred in a clinical trial of Pfizer for the treatment of Duchenne muscular dystrophy (DMD) . This clinical trial, also using an adeno-associated virus (AAV9) vector, the difference is that instead of sequencing through CRISPR gene editing, this clinical trial uses an AAV vector to deliver a Mini-Dystrophin encoding a miniature dystrophin Gene.

CRISPR gene editing technology has only been born for 10 years, and gene therapy has only been around for more than 20 years. Any death of CRISPR gene editing and gene therapy during clinical trials is an opportunity to think about these fields.

When a brave man dies, in addition to grieving for him, we learn from it as much as we can, find out what went wrong, and fix it quickly to forge a path forward.

References :

A DMD patient died after receiving CRISPR gene-editing therapy: Autopsy results show, or from an immune response to AAV vector.

(source:internet, reference only)

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Important Note: The information provided is for informational purposes only and should not be considered as medical advice.