High Cholesterol CRISPR Cure Enters Human Trial

New CRISPR based gene therapy aims to permanently deactivate a gene in the liver that regulates the production of PCSK9, a protein that prevents the body from removing excess cholesterol. In trials with monkeys, the treatment reduced LDL cholesterol levels by 70% in two weeks.

A clinical trial volunteer in New Zealand has become the first person to undergo DNA editing to lower their blood cholesterol, a development that may portend widespread use of the technology to prevent heart attacks.

A version of the gene-editing tool CRISPR was injected into the patient's liver cells as part of a clinical trial conducted by the US biotechnology company Verve Therapeutics to modify a single letter of DNA.

The company believes that this relatively minor adjustment should be sufficient to permanently lower a person's levels of "bad" LDL cholesterol, the fatty molecule that is responsible for the gradual hardening of the arteries over time.

The New Zealand patient had an inherited predisposition to high cholesterol levels and was already suffering from heart disease. The company, on the other hand, is of the opinion that the same method could potentially be used in the future to protect millions of people from developing cardiovascular disease.

"If this works and is safe, this is the cure for a heart attack," says Sekar Kathiresan, CEO of Verve and gene researcher who founded the company three years ago.

It's been ten years since scientists developed CRISPR, a technology for making targeted changes to DNA in cells, but until now, the method has only been used on patients with rare diseases, such as sickle-cell anemia, in exploratory trials.

Worldwide, atherosclerotic cardiovascular disease is the leading cause of death. Large portions of the global population have LDL levels that are too high, but many individuals are unable to bring it under control. Verve's successful experiment could signal a vast expansion of gene editing to prevent common diseases.

According to Eric Topol, a cardiologist, and researcher at Scripps Research, this genome editing technique has the potential to have the greatest impact due to the number of people who could benefit.

Some physicians believe aggressively lowering LDL and maintaining a low level throughout life could prevent cardiovascular disease-related deaths. Eugene Braunwald, a physician at Brigham and Women's Hospital in Boston and advisor to Verve, holds this opinion.

"The lower the LDL, the better," Braunwald explains. "The LDL cannot be too low. The issue is how to write it down."

A strict diet can be beneficial, such as one that excludes eggs, meat, and even olive oil. However, few people can maintain it. Statins are the medications that are prescribed the second most frequently to patients in the United States. These pills can halve a person's LDL, but some people cannot tolerate the side effects, and others find it challenging to take a medication daily.

Some biotechnology-based medications require injections twice a month or even twice a year. Recently, Dr. Braunwald pondered what would happen if these drugs were widely administered as a public health intervention, similar to the annual influenza vaccine. "I estimate that if you begin taking it at age 30, you will live without coronary artery disease until age 100," he says.

LDL is the primary cause of atherosclerotic cardiovascular disease, which is the leading cause of death in industrialized nations. However, these medications are not yet widely utilized. They remain expensive, continue to be inconvenient, and insurers refuse to pay. "Therefore, gene editing is the biggest stick, as it is permanent. "You are never required to return," says Braunwald.

Here in Verve's clinical trial site in New Zealand, where the trial is being conducted, 40 individuals with familial hypercholesterolemia (FH), an inherited form of high cholesterol, will receive gene therapy. Even as children, those with FH can have cholesterol levels that are twice the norm. Many only discover they have a problem when they suffer a heart attack, often at a young age.

The study also represents the first application of base editing, a novel adaptation of CRISPR developed in 2016. In contrast to traditional CRISPR, which cuts a gene, base editing replaces a single DNA letter with another.

The gene being modified by Verve is called PCSK9. It plays a significant role in maintaining LDL levels, and the company claims that its treatment will deactivate the gene by introducing a single-letter error.

Kathiresan was a geneticist at the Broad Institute in Cambridge, Massachusetts, searching for inherited causes of heart disease prior to founding Verve. He founded Verve after his brother, Senthil, died suddenly of a heart attack; he believed that base editing could prevent such tragedies.

The fact that Verve's base-editing technique is substantially similar to mRNA vaccines for covid-19 is one of the primary reasons for its rapid development. Similar to vaccines, the treatment consists of genetic instructions encased in a nanoparticle, which transports the instructions into a cell.

While the vaccine instructs cells to produce a component of the SARS-CoV-2 virus, the particles in Verve's treatment carry RNA instructions for a cell to assemble and target a base-editing protein, which then modifies the cell's copy of PCSK9, thereby introducing a small error.

In experiments conducted on monkeys, Verve discovered that the treatment reduced bad cholesterol by 60%. In animals, the effect has persisted for over a year and may be permanent.

The human experiment may involve some danger. Nanoparticles are somewhat toxic, and there have been reports of individuals taking other medications to reduce PCSK9 experiencing adverse effects, such as pain in their muscles when exposed to nanoparticles. And while treatment with conventional drugs can be discontinued if complications arise, there are currently no plans to reverse gene editing.

The few gene therapies currently available on the market cost hundreds of thousands of dollars. However, Verve's should be significantly less expensive, especially if used frequently. The delivery of genes in other gene therapies is accomplished through the use of viruses that have been specially prepared, whereas the production of nanoparticles involves a chemical process that is more scalable."

The pandemic and the emerging need for vaccines created large-scale manufacturing capacity," says Kiran Musunuru, a gene-editing specialist at the University of Pennsylvania and co-founder of Verve. He says this capacity "can be easily repurposed for genetic therapy," and "abundant capacity naturally results in lower prices."

Musunuru claims that people are even considering "booster shots" in the event that the initial round of gene editing is not successful or to knock out additional cholesterol genes and intensify the effect on LDL.

The founders of Verve are fortunate in that the leading cause of death in the world is also the first common problem that gene editing can solve. Kathiresan, who takes a statin to keep his LDL levels under control, believes gene editing for cholesterol could be a life-extension treatment.

"The leading cause of death worldwide is a heart attack," he says. People will live longer if they are administered a medication that prevents heart attacks.

                            First patient dosed with VERVE-101, a CRISPR gene editing medicine that can reduce bad cholesterol