The Gene editing story : The sickest of the sick were the ten patients who signed up for the experimental medication trial.Each of them had a hereditary condition that caused their blood levels of LDL cholesterol to rise. LDL cholesterol, sometimes referred to as “bad cholesterol,” is notorious for blocking arteries.
Heterozygous familial hypercholesterolemia, the patient’s illness, can cause severe heart disease and even death if left untreated at a young age. From birth, their arteries had been immersed in excessive levels of LDL cholesterol. Even common cholesterol-lowering medications were unable to get the levels “even remotely under control” in a number of patients, according to Andrew Bellinger, chief scientific officer of Verve Therapeutics, a biotechnology company based in Boston, and cardiologist.
His group has now attempted a novel strategy: VERVE-101, a genetic medication that blocks a gene that increases cholesterol. The medication inactivates the gene by erasing one DNA letter and writing another, acting as a sort of molecular pencil. one unique genetic alteration. just one prescription drug. A potential treatment that lasts a lifetime.
At least, that is the hope. In November, Bellinger gave a presentation at the American Heart Association meeting on the findings of a small clinical experiment named Heart-1. According to Bellinger, VERVE-101 successfully reduced LDL cholesterol. It is the first demonstration that a spelling alteration in a person’s DNA made inside their body might have this kind of impact. “A single dose can lead to clinically meaningful reductions in LDL levels,” he declared.
“This whole concept of ‘one and done’ is amazing,” says Pam Taub, a cardiologist at the University of California, San Diego, who was not involved with the experiment. People with familial hypercholesterolemia have lifetime symptoms. These people will always need to take their prescriptions. A medication like VERVE-101, which is administered to change a person’s DNA, may require a modification in the treatment plan.
Taub raises concerns over the safety of VERVE-101. Heart attacks struck one trial participant. A heart arrest claimed the life of another. Bellinger stated that the death had nothing to do with the course of therapy.
According to UCLA’s David Geffen School of Medicine cardiologist Karol Watson, who was not involved in the new work, proving VERVE-101’s safety going forward is imperative. 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 during the meeting. “You are permanently altering the genome.”
Here is what we now know about four important facets of the new medication’s development.
VERVE-101 is dependent on a base editor, a protein that modifies DNA.
The components of VERVE-101 are straightforward. It’s basically two kinds of RNA molecules, which are DNA’s molecular cousins, wrapped together in a big bubble.
Once injected into the bloodstream, the medication enters the liver and diffuses into the cells. One of the RNA molecules urges cells to make a protein called an adenine-base editor. The other serves as the editor protein’s genetic GPS, directing it to the appropriate region of DNA.
It utilises CRISPR 2.0 technology. By cutting across DNA strands, first-generation CRISPR/Cas9 instruments function like molecular scissors and can damage genes (SN: 8/14/19). Molecular pencils are more akin to base editors. They alter DNA by changing one base for another, doing chemistry on a single DNA letter, and generating a new genetic sequence (SN: 10/25/17).
“Base editors change a sequence that you choose into a different sequence of your choosing,” explains Howard Hughes Medical Institute investigator David Liu, a chemist at Harvard University whose team pioneered the technology in 2016. The PCSK9 gene, which contains the sequence responsible for VERVE-101, contains instructions for producing a protein that elevates blood cholesterol levels. PCSK9 can be turned off with a single edit in a specific spot.
Less than a week after the injection, editing is completed, and the medication degrades quickly, according to Bellinger. After breaking down along with its RNA cargo, the fat bubble known as a lipid nanoparticle, VERVE-101 disappears from the body in a matter of weeks. “The only thing that’s left is the DNA change you made to the PCSK9 gene,” he added.
A desirable target for gene-editing therapy is PCSK9.
According to Parag Joshi, a preventive cardiologist at UT Southwestern Medical Centre in Dallas who was not involved in the experiment, PCSK9 has been a popular therapeutic target for the past ten or so years.
Scientists were aware that certain individuals have mutations in PCSK9 that cause the gene to be turned off. These people tended to have lower LDL cholesterol levels and significantly less heart disease, according to research by geneticist Helen Hobbs, an HHMI investigator at UT Southwestern Medical Center, and colleagues published in 2006.
The field advanced because of that seminal work, according to Joshi. Suddenly, researchers have evidence that human health could be maintained in the absence of PCSK9. According to Joshi, this makes it “a very attractive drug target.” According to the suggestion, turning off PCSK9 wouldn’t be harmful and might even be beneficial by reducing the risk of heart disease.
Usually, the PCSK9 protein breaks down the LDL receptor protein. One of the good guys, this receptor takes harmful cholesterol from the blood and transfers it to the liver cells, where it is eliminated. Blood levels of LDL cholesterol rise when there are insufficient LDL receptors.
In short, PCSK9 causes sickness, according to cardiologist and Verve CEO and cofounder Sekar Kathiresan. “All you get is health if you turn it off.”
Currently, there are a few treatments that target PCSK9, such as injectable antibodies or an RNA-based medication that inhibits PCSK9 synthesis. Joshi recommends that patients take a daily statin medication to reduce their LDL cholesterol. But frequently, it’s insufficient.
Furthermore, despite the fact that the treatments are potentially helpful for those with familial hypercholesterolemia, “very few patients are actually on these medications,” according to Kathiresan.
According to his team, this is because patients are being asked to take daily medications or sporadic injections for decades, which is simply too much of a strain. According to Kathiresan, “that model doesn’t seem to be working.” And that’s what our goal is to resolve.
Early results from the VERVE-101 clinical trial point to possible advantages as well as hazards.
Ten individuals, the majority of whom had significant cardiac disease and had heterozygous familial hypercholesterolemia, received a single IV infusion of VERVE-101 from Kathiresan’s team. The blood levels of low-density lipoprotein (LDL) cholesterol reduced dramatically, by 39 to 55 percent, among those who received the highest medication doses examined. And the decline seems to be permanent, according to Bellinger. LDL cholesterol levels remained constant for 180 days following VERVE-101 infusion in the patient receiving the maximum dosage.
Considering the team’s prior successes with nonhuman primates, Bellinger described the outcomes as “pretty much what we expected and planned.” However, despite being preliminary, the new patient data puts the medication on the verge of something greater. According to Kathiresan, “this opens the door for an entirely new way to treat heart disease.”
The safety of VERVE-101 will ultimately determine its usefulness. Throughout the experiment, the group noticed a few possible warning signs. Four patients experienced mild fever and headaches as a result of the IV infusion. However, during the heart meeting, talk turned to something more serious. One patient suffered a heart attack one day following the treatment. Another patient passed away five weeks following the treatment due to an abrupt stoppage of their heartbeat.
According to Kathiresan, the patient’s underlying cardiac condition was most likely the cause of that incident. According to him, an impartial data safety monitoring board that looked at the incidents came to that judgement.
However, the monitoring board concluded that since the heart attack occurred so quickly after dosage, it might have been connected to the medication. However, Kathiresan points out that the patient had been complaining of chest problems before the trial, which they failed to disclose to the study’s researchers.
According to UCSD cardiologist Taub, these are “very, very sick patients.” She believes that these patients ought to be kept out of any further drug studies.
Now, the Kathiresan-led team wants to recruit people with less serious illnesses. Also, in an effort to weed out individuals who are at exceptionally high risk of having a heart attack, they will check the patients’ arteries for blockages.
The business intends to register additional patients at the two highest doses in 2024 in order to decide which dose to proceed with. Additionally, VERVE-102, a different kind of medication that employs a different lipid nanoparticle, is being tested by the researchers. Verve intends to forward one of the medications to a bigger clinical study in 2025, contingent on those outcomes. If the treatment proves effective for those with familial hypercholesterolemia, the company plans to extend its reach to a wider range of patients, including those who do not have the hereditary illness.
It takes time to develop new medications, according to Kathiresan. According to him, it can take over ten years for a drug to be developed into a prescription drug that doctors can prescribe. 2018 saw Verve begin work on its PCSK9 editing project. By the end of the decade, according to Kathiresan, he aims to have an approved drug.
One of the several base editing medications presently undergoing clinical testing is VERVE-101.
Inadvertent alterations to DNA are one possible side effect of gene-editing treatments. Targeting PCSK9, VERVE-101 raises the question, “What if it strays to a different spot in the genome?” from endocrinologist Anne Goldberg of Washington University School of Medicine in St. Louis. She remarks, “The technology looks interesting, but more data is needed.”
An incorrect DNA alteration may increase a person’s risk of cancer. Bellinger stated, “We think that risk is very low” with VERVE-101. According to him, the majority of the company’s efforts are focused on proving that “we do not make edits elsewhere in the genome.”
Harvard’s Liu, who was not part in the trial, claims that base editors today, like the one in VERVE-101, are far better than they were in the early days of the technology. “They have very little off-target editing and very high on-target editing efficiency.”
There are currently five more base-editing clinical trials underway that are aimed at treating different illnesses like leukaemia and sickle-cell disease. Liu believes that patients would have “a completely new lease on life” as a result of the gene-editing drugs.
According to Bellinger, his group views VERVE-101 as a one-time medical treatment, akin to “molecular surgery without a scalpel.” Although it is theoretically feasible to undo the alteration that VERVE-101 made, this is not how he and his colleagues see it.
The goal is to provide individuals with familial hypercholesterolemia with a therapeutic option that does not require daily administration of statin pills, according to cardiologist Donald Lloyd-Jones, who was not involved in the experiment. “They might consider it as an option,” according to Lloyd-Jones of Northwestern University Feinberg School of Medicine in Chicago, regarding a treatment like VERVE-101.
“I think this would be a very interesting approach to a lifetime fix,” he stated during the meeting, “if we get those safety data, if we get those efficacy data.”