[The trial involved only 10 patients, but it suggests cholesterol
can be permanently reduced with a single treatment for patients at
risk of heart disease]
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NEW GENE EDITING TREATMENT CUTS DANGEROUS CHOLESTEROL IN SMALL STUDY
 
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Gina Kolata
November 12, 2023
New York Times
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_ The trial involved only 10 patients, but it suggests cholesterol
can be permanently reduced with a single treatment for patients at
risk of heart disease _

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The handful of patients had severe heart disease that had caused chest
pain and heart attacks. After trying available cholesterol-lowering
medications, they could not get their cholesterol as low as
cardiologists recommended.

So they volunteered for an experimental cholesterol-lowering treatment
using gene editing that was unlike anything tried in patients before.

The result, reported Sunday by the company Verve Therapeutics of
Boston at a meeting of the American Heart Association, showed that the
treatment appeared to reduce cholesterol levels markedly in patients
and that it appeared to be safe.

The trial involved only 10 patients, with an average age of 54. Each
had a genetic abnormality, familial hypercholesterolemia,
that affects
[[link removed]] around
one million people in the United States. But the findings could also
point the way for millions of other patients around the world who are
contending with heart disease, which remains a leading cause of death.
In the United States alone, more than 800,000 people have heart
attacks each year.

And while more trials in a broader range of patients will need to be
carried out, gene editing experts and cardiologists said the treatment
had the potential to transform preventive cardiology.

“Even for seasoned veterans of this field like myself, this is a day
we will look back on,” said Fyodor D. Urnov, a gene editor at the
Innovative Genomics Institute in Berkeley, Calif. “I see today as
crossing a Rubicon, in a good way. This is not a small step. It is a
leap into new territory.”

Impressed with the data and the potential it shows, the pharmaceutical
giant Eli Lilly paid $60 million to collaborate with Verve
Therapeutics and opted to acquire additional rights to Verve’s
programs for an additional $250 million. If the editing continues to
look promising, Eli Lilly expects to help with larger studies.

“Until now, we thought of gene editing as a treatment we should
reserve for very rare diseases where there is no other treatment,”
said Dr. Daniel Skovronsky, Eli Lilly’s chief scientific and medical
officer. “But if we can make gene editing safe and widely available,
why not go after a more common disease?”

The new study was led by Dr. Sekar Kathiresan, chief executive of
Verve. Patients received a single infusion of microscopic lipid
nanoparticles containing within them a molecular factory to edit a
single gene in the liver, the site of cholesterol synthesis. The gene,
PCSK9, raises levels of LDL cholesterol, the bad kind. The plan was to
block it.

The little lipid spheres were carried through the blood directly to
the liver. They entered liver cells and opened up, revealing two
molecules. One instructs DNA to make a gene editing tool, and the
other is a guide to take the editing tool to the gene that needs
editing.

The treatment “is almost like science fiction,” said Dr. Martha
Gulati, director of preventive cardiology at the Smidt Heart Institute
of Cedars-Sinai Medical Center in Los Angeles and president of the
American Society for Preventive Cardiology, who was not involved in
the trial.

The gene editing tool acts like a pencil and an eraser. The eraser
wipes out one letter of the target gene, and the pencil writes in a
new one, turning off PCSK9.

The goal: a single cholesterol-lowering treatment that results in
lifelong protection from heart disease.

Patients received varying doses. LDL levels in the three who received
the highest doses fell by 39 to 55 percent — enough to get them
toward their cholesterol goal.

In the small study, those who received the higher doses had flulike
symptoms for a few hours. Two patients had serious adverse events that
the study’s independent data safety and monitoring board deemed a
result of their underlying severe heart disease. The board advised the
researchers not to stop the study.

One had a fatal cardiac arrest five weeks after receiving the
infusion. An autopsy showed that several of his coronary arteries were
blocked.

The other patient had a heart attack the day after the infusion. It
turned out that he had been having chest pain before receiving the
infusion but had not reported it. If the investigators had known, he
would not have received the treatment.

In a way, the treatment is a culmination of studies
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began a decade ago when researchers discovered rare but healthy
individuals with cholesterol levels that seemed impossibly low. The
reason was that their PCSK9 gene was mutated and no longer functioned.
As a result, these people were protected from heart disease.

That led to the development of antibodies to block the gene. Patients
inject themselves with the antibodies once a week. Then came a
twice-yearly RNA injection that prevents PCSK9 from being made.

It seemed possible that those treatments, as well as statins for those
whose cholesterol is more easily controlled, could help solve the
heart disease problem.

But heart disease persists as a killer. Even after people are
diagnosed with heart disease, less than 60 percent
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all patients take a statin. Only a quarter take one of the more
effective, high-intensity statins, Dr. Gulati said.

“Patients take it initially, and then they forget or decide they
don’t need it,” she explained. “That happens more than you’d
think.”

Dr. Michelle O’Donoghue, a cardiologist at Brigham and Women’s
Hospital, said that because patients so often do not take their pills
or injections, “there is a lot of interest, through gene editing, of
a one and done — a single treatment and a lifetime response.”

Family history was the inspiration for Dr. Kathiresan at Verve
Therapeutics. His uncle and grandmother died of heart attacks. His
father had a heart attack at age 54. And then, on Sept. 12, 2012, his
42-year-old brother, Senthil, returned from a run dizzy and sweaty. He
was having a heart attack. He died nine days later.

At that moment, Dr. Kathiresan said, he vowed to find a way to prevent
what had happened to his brother from happening to anyone else.

Of course, even if gene editing works, applying it to young people
with heart risk is well into the future. But, Dr. Gulati said, early
gene editing of younger patients with genetically high cholesterol
levels might prevent arteries from hardening.

“It could be an incredible medicine,” she said.

All this depends on success and safety of the gene editing and on its
effects lasting. The first patient was treated just six months ago.
But a previous study in monkeys lasted two and a half years, and the
results of the gene editing persisted.

Dr. Urnov, who said he has a genetic risk for heart disease, is
optimistic for himself and his 6-year-old daughter.

“I honestly cannot wait for this medicine to become available for
heart disease prevention,” he said. “I love the idea of having
gene editing as a vaccine for the prevention of heart disease.”

_Gina Kolata [[link removed]] reports on
diseases and treatments, how treatments are discovered and tested, and
how they affect people. She has been a Pulitzer finalist and has
written several books. More about Gina Kolata
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