High cholesterol: New CRISPR treatment enters human trial

  • Cardiovascular disease is the number one cause of death in the world.
  • High cholesterol is a modifiable risk factor for heart-related diseases.
  • Biotechnology company Verve Therapeutics recently launched an in-human clinical trial for a gene-editing medication aimed at lowering cholesterol.

Cardiovascular disease is the number one cause of death worldwide. In 2019, about 17.9 million people worldwide died from heart-related diseases.

A common and modifiable risk factor for cardiovascular disease is high cholesterol. Past research shows if a person reduces their cholesterol by 10%, they can lower their risk for heart-related issues by up to 30%.

Although there are currently medications available to help lower cholesterol, they can sometimes have side effects. Additionally, these therapies normally require a person to take them every day, which causes decreased prescription adherence for some patients.

To provide a different type of treatment for lowering cholesterol, biotechnology company Verve Therapeutics has recently launched a clinical trial in New Zealand to test a new single-dose gene-editing medication in human patients.

What is CRISPR used for? 

The base of Verve Therapeutics’ new treatment is genetic editing tool called CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats. Through the use of this technology, it is possible to change a person’s DNA and ultimately alter how certain genes function.

CRISPR technology uses the same type of gene editing bacteria naturally used as a defense mechanism. If a bacteria becomes infected by a virus, it takes a small piece of the virus’s genetic code. It then inserts that small piece of code into its DNA in a specific pattern called a CRISPR array. If the virus attacks again, the bacteria can now recognize the virus and make pieces of RNA that attack the virus’ DNA, helping to protect the bacteria from infection.

The CRISPR gene editing tool was first discovered in 2012. Since then, researchers have used the technology in multipple mouse-model studies as a treatment for diabetes, HIV, and muscular dystrophy.

In 2017, scientists used CRISPR technology to repair a disease-causing mutation in viable human embryos.

In 2016, Chinese scientists were the first to deliver a CRISPR therapy to a human to test the use of CRISPR gene editing in people with lung cancer.

Since then, there have been more human trials with therapies based on CRISPR technology. In March 2020, a human received CRISPR-based gene therapy during a clinical trial for the eye disease Leber’s congenital amaurosis 10. And in 2021, conducted a clinical study for a CRISPR treatment for sickle cell disease.

PCSK9 gene therapy for HeFH

The current clinical trial for Verve Therapeutics’ VERVE-101 gene editing treatment, known as the heart-1 clinical trial, examines the medication as a treatment for patients with heterozygous familial hypercholesterolemia (HeFH).

HeFH is an inherited genetic disorder affecting the liver and ultimately causing very high levels of cholesterol in the body if not treated. HeFH is a subtype of atherosclerotic cardiovascular disease (ASCVD), where blood vessel walls become thick and hard, making it difficult for blood to flow freely.

According to Verve Therapeutics’ website, VERVE-101 works by targeting a specific gene in the liver called the PCSK9 gene. The treatment edits the PCSK9 gene to turn it off. This results in lower levels of “bad” cholesterol — known clinically as LDL-C — in the blood.

“Our ultimate goal with VERVE-101 is to bring a new option to the millions of people with ASCVD around the world, and dosing participants in the Phase 1 study for this first indication, HeFH, is a key inflection point to achieving that goal,” said Dr. Andrew Bellinger, chief scientific and medical officer of Verve, in a press release.

“With the current standard of care treatment for HeFH, less than 20% of patients achieve LDL-C goal levels due to the limitations of the chronic model which requires rigorous patient adherence, regular health care access, and extensive health care infrastructure. VERVE-101 has the potential to change the way cardiovascular disease is cared for by lowering LDL-C as low as possible for as long as possible after a single treatment,” he stated in the release.

The clinical trial reportedly includes 40 adult patients with HeFH and established ASCVD. Verve Therapeutics plans to release clinical trial data in 2023.

Before launching this clinical study, Verve Therapeutics released preclinical data from its study of VERVE-101 on non-human primates. The company presented these findings at the TIDES USA 2022 Oligonucleotide & Peptide Therapeutics Conference in May 2022.

Preclinical data reportedly showed a more than 60% mean reduction in LDL-C after 20 months of a non-human primate receiving a single dose of the therapy.

CRISPR and future of cholesterol treatment

MNT spoke with Dr. Christie Ballantyne, chief of cardiology and cardiovascular research at Baylor College of Medicine. He commented this is an exciting first step in research to examine if single-base gene editing would offer lifelong lowering of LDL-C.

“Gene editing would offer potentially a one-time treatment and overcome the problems that we face with adherence to chronic treatment of lipids,” Dr. Ballantyne explained.

Dr. Rigved Tadwalkar, a board certified cardiologist at Providence Saint John’s Health Center in Santa Monica, CA, agreed.

“The biggest problem we have with currently available therapies for lowering cholesterol is that adherence is low,” Dr. Tadwalkar explained to MNT. “This is for several reasons, but chiefly the standard of care, which are statins, need to be taken daily. And there are many people who aren’t great with following that routine.”

“What’s nice about therapy like this is that the chronic aspect of cholesterol management is essentially taken out of the equation. Compliance is no longer a problem if this type of therapy works, which is truly staggering.”

– Dr. Rigved Tadwalkar

When asked what the potential risks for a gene-editing therapy might be, Dr. Tadwalkar stated although the technology should be safe, there are some concerns to consider.

“The concern is that if an off-target base is edited and renders a different and possibly important gene nonfunctional, or worse yet causes some other terrible anomaly, this could really be devastating theoretically,” he detailed. “While this shouldn’t happen, the specific effects of a therapy in a human can often be different than that as seen in other organisms, so we can’t just extrapolate based on information that we have from other organisms. There’s also an aspect of irreversibility associated with this that should be taken into account.”

“I honestly feel like if it works as intended, it should not present a large issue, as we have seen with other PCSK9-based therapies,” Dr. Tadwalkar added. “When we remove this protein, people tend to do very well, and we have great long-term outcomes.”

And Dr. Ballantyne said he would like to see data on the efficacy and tolerability of the CRISPR-based treatment and dose-response after the clinical trial concludes.

“Phase 1 trials are very small and not powered to tell us much about safety — this issue requires much larger and longer studies,” he added.

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