PHILADELPHIA — Ten patients enrolled in the experimental drug trial, and they were the sickest of the sick.
All had a genetic disorder that cranks up levels of LDL cholesterol in the blood. Known as “bad cholesterol,” LDL cholesterol is infamous for clogging arteries. The patients’ disorder, called heterozygous familial hypercholesterolemia, can lead to severe heart disease at an early age — and death.
Their arteries had been bathing in high LDL cholesterol since birth. In several patients, even typical cholesterol-lowering drugs couldn’t get the levels “even remotely under control,” says Andrew Bellinger, a cardiologist and chief scientific officer at Verve Therapeutics, a Boston-based biotechnology company.
Now, his team has tried a new approach: a genetic medicine called VERVE-101 designed to turn off a cholesterol-raising gene. Using a kind of molecular pencil, the medicine erases one DNA letter and writes in another, inactivating the gene. A single genetic change. A single medication. A potential treatment that lasts a lifetime.
That’s the hope, anyway. Bellinger presented the results of a small clinical trial called heart-1 at the American Heart Association meeting in November. VERVE-101 successfully lowered LDL cholesterol, Bellinger reported. It’s the first time anyone has shown that a DNA spelling change made inside a person’s body could have such an effect. “We can achieve clinically meaningful LDL reductions with a single dose,” he said.
Now, his team has tried a new approach: a genetic medicine called VERVE-101 designed to turn off a cholesterol-raising gene. Using a kind of molecular pencil, the medicine erases one DNA letter and writes in another, inactivating the gene. A single genetic change. A single medication. A potential treatment that lasts a lifetime.anyone has shown that a DNA spelling change made inside a person’s body could have such an effect. “We can achieve clinically meaningful LDL reductions with a single dose,” he said.
People with familial hypercholesterolemia have lifelong symptoms, so “this whole concept of ‘one and done’ is really amazing,” says Pam Taub, a cardiologist at the University of California, San Diego who was not involved with the trial. These patients must take medications their entire lives. An infused drug like VERVE-101 — designed to alter a person’s DNA — could change treatment strategy.
Taub points out questions about VERVE-101’s safety. One trial patient had a heart attack. Another died due to cardiac arrest. But that death was not related to treatment, Bellinger said.
Moving forward, establishing VERVE-101’s safety is crucial, agreed Karol Watson, a cardiologist at the David Geffen School of Medicine at UCLA who wasn’t involved with the new work. Editing people’s DNA to lower their cholesterol “is a strategy that could be revolutionary, but we have to make sure it’s safe,” she said at the meeting. “You are changing the genome forever.”
Here’s what we know about four key aspects of the new medicine and its history.
VERVE-101 relies on a DNA-modifying protein called a base editor
The composition of VERVE-101 is simple. It’s just two types of RNA molecules — molecular cousins of DNA — bundled inside a bubble of fat.
Infused into the bloodstream, the drug travels to the liver and slips into cells. One of the RNA molecules tells cells to build a protein called an adenine base editor. The other acts as a genetic GPS, guiding the editor protein to the correct stretch of DNA
The technology is CRISPR 2.0. First generation CRISPR/Cas9 tools act like molecular scissors and can disrupt genes by snipping through DNA’s strands (SN: 8/14/19). Base editors are more like molecular pencils. They edit DNA by performing chemistry on an individual DNA letter, or base, rewriting for another creating a new genetic sequence
“Base editors actually change a sequence that you choose into a different sequence of your choosing,” says Howard Hughes Medical Institute investigator David Liu, a chemist at Harvard University whose team [nvented technology in 2016 In the case of VERVE-101, that sequence is inside the PCSK9 gene, which encodes instructions for manufacturing a protein that raises blood cholesterol levels. Just one edit in a precise location shuts PCSK9 down.
Editing wraps up less than a week after the infusion, and the drug breaks down rapidly, Bellinger said. Both the fat bubble, called a lipid nanoparticle, and its RNA cargo degrade, and within a few weeks, VERVE-101 vanishes from the body. “The only thing that’s left is the DNA change you made to the PCSK9 gene,” he said.
PCSK9 is a tempting target for gene-editing therapy
PCSK9 has been a hot therapeutic target for the last decade or so, says Parag Joshi, a preventive cardiologist at UT Southwestern Medical Center in Dallas who was not part of the trial.
Researchers knew that some people have PCSK9 mutations that switch the gene off. These people tended to have lower levels of LDL cholestrol and drastically have less heart disease geneticist Helen Hobbs, an HHMI investigator at UT Southwestern Medical Center, and colleagues reported in 2006.
That landmark study pushed the field forward, Joshi says. Suddenly, scientists had proof that people could live healthy lives when PCSK9 was inactivated. That made it “a very attractive drug target,” Joshi says. It suggested that disabling PCSK9 would do no harm — and could even help, by lowering the risk of heart disease.
Typically, the PCSK9 protein breaks down another protein called the LDL receptor. This receptor is one of the good guys; it keeps bad cholesterol in check by snatching it from the blood and transporting it into liver cells for disposal. Without enough LDL receptors, LDL cholesterol levels in the blood ratchet up.
Sekar Kathiresan, a cardiologist and Verve’s CEO and cofounder puts it succinctly: PCSK9 causes disease. “If you turn it off, all you get is health.”
Today, a few existing therapies target PCSK9, including injected antibodies or an RNA-based drug that shuts down production of the protein. Patients should take a daily statin pill to lower LDL cholesterol, Joshi says. But it’s often not enough.
And though the therapies are theoretically effective for people with familial hypercholesterolemia, Kathiresan says, “very few patients are actually on these medications.”
His team thinks that’s because the current approach is just too heavy a burden — asking patients to take daily pills or intermittent injections for decades. “That model doesn’t seem to be working,” Kathiresan says. “And that’s what we’re trying to fix.”
Early VERVE-101 clinical trial results reveal potential benefits — and risks
Kathiresan’s team gave a single IV infusion of VERVE-101 to 10 people with heterozygous familial hypercholesterolemia, most of whom had severe heart disease. In those who received the highest drug doses tested, blood levels of LDL cholesterol dropped sharply, by 39 to 55 percent. And the drop appears long-lasting, Bellinger said. For the patient at the highest dose, LDL cholesterol levels held steady for 180 days after VERVE-101 infused into the bloodstream.
Steep reductions
In a clinical trial with 10 participants, people who received the highest doses of VERVE-101 tested (green and purple dots) saw steep reductions in the amount of LDL cholesterol in the blood.
