A DMD patient died after receiving CRISPR gene-editing therapy, raising concerns about the future of gene-editing therapies

The emergence and application of CRISPR gene editing technology has brought unprecedented hope for the treatment of genetic diseases, and in recent years, we have also seen the clinical progress of CRISPR gene editing in rare genetic diseases, cancer, and cardiovascular diseases, which has given hope
to many families facing rare and devastating diseases.

Recently, a 27-year-old Duchenne muscular dystrophy (DMD) patient named Terry Horgan tragically passed away after receiving CRISPR gene-editing treatment delivered by an adeno-associated virus (AAV9) vector, and although it is not clear the real cause of Terry Horgan's death and whether it is related to CRISPR, its death has undoubtedly raised concerns and questions
about the future of CRISPR gene-editing therapy.

Terry Horgan and his family, image from Cure Rare Disease

Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-chromosome recessive disorder that occurs
mainly in boys.
According to statistics, about 1 in every 3,500 newborn male babies worldwide suffers from this disease
.
Patients usually begin at 3 to 5 years of age, presenting with progressive leg muscle weakness at the earliest, leading to difficulty walking
.
Usually loses the ability to walk at the age of 12, begins to develop heart and respiratory weakness during adolescence, and leads to serious complications, usually dying
from respiratory and heart failure between the ages of 20-30 years.

As a monogenic disorder, Duchenne muscular dystrophy (DMD) is caused by mutations in the Dystrophin gene encoding dystrophin on the X chromosome, which is unable to produce sufficient or healthy dystrophin and the patient's muscle tissue is gradually replaced
by fat and fibrotic tissue.

Custom CRISPR gene-editing therapies

Terry Horgan, the protagonist of this article, was diagnosed with Duchenne muscular dystrophy (DMD) at the age of 3, and in 2017, Terry's older brother, Richard Horgan, founded a nonprofit called Cure Rare Disease to help rare disease patients
like Terry.

Terry (left) and his brother Richard (right)

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

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

The Dystrophin gene is huge, with as many as 79 exons, and mutations in different exons can cause DMD
.
Because the gene is too large, delivering the correctly encoded Dystrophin gene directly into the cell doesn't work
.
For Terry, he is an exome 1 deletion mutation in the Dystrophin gene, and CRD-TMH-001 therapy hopes to stabilize or reverse the progression
of DMD by promoting the expression of the homoform of the anti-dystrophin homoform encoded by the Dystrophin gene through CRISPR technology.

The patient tragically passed away

Terry has said that he has loved computers since he was a child, and when he can still walk, he tries to build computers
by himself.
He then studied information science at Cornell University and stayed on to work in the information science department at
Cornell University.

As his condition progressed, he had to rely on electric wheelchairs to move, and he said his fear of the disease began to increase
.
But he didn't participate in any clinical trials of the treatment until this gene-editing therapy
customized for him.

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

However, on October 14, 2022, Cure Rare Disease announced Terry's tragic death
.
Terry Horgan, the younger brother of Cure Rare Disease founder and CEO Richard Horgan, who participated in a clinical trial of a new CRISPR gene-editing therapy CRD-TMH-001, died tragically, and the cause
of his death is not yet clear.
The loss of Terry is heartbreaking, and he will 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 the situation to the FDA and is currently working with 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.
It is expected to take 3-4 months to draw a complete conclusion
.

Moving forward in tragedy

In fact, deaths in clinical trials are not uncommon because the clinical trials themselves are exploratory and many of the people who participate in clinical trials are already seriously ill
.

In 1999, in the early days of gene therapy research, an 18-year-old teenager, Jesse Gelsinger, tragically died after receiving adenovirus gene therapy for ornithine carbamoyltransferase deficiency (OTC), becoming the first person
in the world to die from gene therapy.
Follow-up studies showed that adenovirus vectors caused him to develop severe immune responses and multiple organ failure
.
His tragedy led the FDA to begin rigorous review of gene therapy clinical trials, when the gene therapy star vector adenovirus gradually declined, and the entire gene therapy field began to fall silent
for 20 years.

Jesse Gelsinger (left), Professor Jim Wilson (right), who led the clinical trial

In the aftermath of this tragedy, Professor Jim Wilson began to work on finding safer gene therapy vectors, discovering and promoting adeno-associated virus (AAV) vectors
.
Terry's clinical trial also used adeno-associated virus (AAV) vectors
.

In 2017 and 2019, the FDA approved two AAV gene therapies for marketing, which began to revive the gene therapy field after 20 years, and now hundreds of AAV gene therapy clinical trials are underway around the
world.

As AAV gene therapy clinical trials progressed, related patient deaths also began to appear, for example, in a Pfizer clinical trial for the treatment of Duchenne muscular dystrophy (DMD) at the end of 2021.

The clinical trial also used adeno-associated virus (AAV9) vectors, except that instead of sequencing the CRISPR gene, the trial used an AAV vector to deliver a mini-dystrophin gene
encoding mini-dystrophin.

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

CRISPR holds new hope for rare disease and cancer patients, and we've seen some inspiring breakthroughs, but CRISPR isn't perfect, and the AAV viral vector used in Terry's treatment could also be the cause of
his death.

When a brave person dies, in addition to grieving for him, we must learn as much as we can from it, find the problem, and solve it quickly to open the way
forward.