In the first human trial of a gene editing process called base editing, it appeared that the technique can help keep levels of cholesterol linked to heart disease at bay.
Listen and subscribe to The L.A. Local podcast: your TL;DR for what's happening in Southern California
However, the treatment does come with side effects and one death was recorded in the trial.
Per an article in the Nature journal, Verve Therapeutics, a biotechnology firm in Boston, Mass., has developed the treatment, called VERVE-101. Participants in the trial were injected with VERVE-101 to permanently deactivate PCSK9, a gene in the liver that controls low-density lipoprotein (LDL) levels, a “key contributor to heart disease,” according to the article.
“Cholesterol is a waxy, fat-like substance that's found in all the cells in your body,” explained the National Library of Medicine. “Your body needs some cholesterol to make hormones, vitamin D, and substances that help you digest foods. Your body makes all the cholesterol it needs. Cholesterol is also found in foods from animal sources, such as egg yolks, meat, and cheese.”
It also said that “if you have too much cholesterol in your blood, it can combine with other substances in the blood to form plaque,” which sticks to the walls of arteries and can lead to coronary artery disease.
With the VERVE-101 treatment, the amount of LDL – also known as “bad cholesterol” – in the blood was reduced by 55% in trial participants.
All of these participants had a condition that caused high lifelong LDL levels.
“It’s a tremendous scientific milestone because it’s the first time that they’ve been able to show that a single base pair of DNA editing, using CRISPR technology in humans, has had a clinical effect,” said Ritu Thamman, a cardiologist at the University of Pittsburgh in Pennsylvania.
CRISPR is short for “clustered regularly interspaced short palindromic repeats” and it refers to technology used to selectively modify DNA.
Previously, researchers engineered donated immune cells in a dish to target a teenager’s leukemia,” then infused them to put her disease into remission so she could get a stem cell transplant,” according to the Science journal. In the VERVE trial, gene editing took place inside the body.
“From the clinical point of view, it has the potential to open a new way of treating coronary artery disease,” said Thamman of VERVE-101.
Instead of taking daily pills, patients could have a one-and-done treatment.
Findings about the treatment were reported Nov. 12 at a meeting of the American Heart Association in Philadelphia. CRISPR-Cas9 machinery was used to chemically change single nucleotide bases without breaking double strands of DNA, a technique developed by a team led by chemical biologist David Liu at Harvard University in 2018. This editing affected enzymes encoded by the gene that prompted receptors for LDL and reduced levels of the cholesterol.
“VERVE-101 consists of two RNA molecules packaged in a lipid nanoparticle — an mRNA molecule that edits adenine bases in DNA and a ‘guide RNA’ molecule to recognize PCSK9. After the treatment is injected, liver cells take up these nanoparticles, and once inside cells they make their way into the nucleii. Then, the base editor makes a single-letter change to the PCSK9 gene sequence, swapping an adenosine base with a guanine base. This turns off the gene and prevents liver cells from producing PCSK9 proteins,” said a detailed description of the process from Nature.
Side effects and criticism
“Two serious adverse events in the trial, including a death, have raised safety concerns, and Verve’s share price plummeted by nearly 40% following the results’ release despite their promise,” said the Nature journal article.
Overall, there were 10 people in the trial who had a life-threatening inherited disease called heterozygous familial hypercholesterolemia (HeFH). The condition causes high LDL levels from birth and it affects more than three million people in the U.S. and Europe. Those who have it can suffer from premature heart attacks, even as children.
“The participants also suffered from severe advanced coronary disease and took maximum doses of lipid-lowering tablets such as statins,” said the Nature journal.
With the treatment, some participants experienced flu-like symptoms such as fever, headaches and body aches. Some also had a temporary increase in liver enzymes that returned to normal within days.
Two of the participants experienced cardiovascular events – one died from a heart attack five weeks after receiving VERVE-101 and another had a heart attack after one day.
“An independent safety board concluded that the first event was expected in people who had such advanced heart disease and was not related to treatment,” said Nature. “The board recommended the trial’s continuation of trial enrolment without changes to the drug protocol.”
Additionally, the journal said that gene-editing approaches carry the risk of “off target” edits at other locations in the genome. No off-target edits were observed in mice by the VERVE-101 team.
While endocrinologist Anne Goldberg of the Washington University School of Medicine in St. Louis said VERVE “could be a game changer,” she also said “CRISPR in humans makes me a bit nervous,” per the Science journal.
Next steps
Verve Therapeutics plans to continue its trial next year in the U.S. since it received approval to enroll participants from the US Food and Drug Administration last month.
The company “aims to select the best therapeutic dose from the trial next year and to launch a phase 2 trial in 2025,” said the Nature journal. Verve must follow trial participants for 14 years, an FDA mandate for gene-editing therapy.
“You are changing the genome forever,” said Karol Watson, a cardiologist at the University of California, Los Angeles. “Safety is going to be of the utmost importance, especially because there are currently safe and efficacious strategies available for lipid lowering.”
Sekar Kathiresan, Verve’s co-founder and chief executive officer, also said the company hopes the treatment will protect against heart attacks and strokes.
“If the blood LDL-cholesterol is very low lifelong, it’s very hard to get a heart attack,” Kathiresan said.
Follow KNX News 97.1 FM
Twitter | Facebook | Instagram | TikTok