New CRISPR treatment is being tested on humans

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

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

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

While medications are currently available to help lower cholesterol, they can sometimes have side effects. In addition, these therapies normally require a person to take them every day, which causes reduced compliance for some patients.

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

The basis of the new treatment from Verve Therapeutics is called the genetic editing tool CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats. By using this technology, it is possible to change a person’s DNA and ultimately change the functioning of certain genes.

CRISPR technology uses the same type of gene-editing bacteria that are naturally used as a defense mechanism. When a bacteria is infected by a virus, a small piece of the virus’s genetic code is needed. It then inserts that little 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 break it into pieces RNA which attack the DNA of the virus and help protect the bacteria from infection.

The CRISPR gene editing tool was first discovered in 2012. Since then, researchers have used the technology in multiple mouse model studies as a treatment for diabetes, HIVand 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 administer CRISPR therapy to a human to demonstrate the use of CRISPR gene editing in people with lung cancer.

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

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

HeFH is an inherited genetic disorder that affects the liver and eventually causes very high cholesterol levels in the body if left untreated. HeFH is a subtype of atherosclerotic cardiovascular disease (ASCVD), in which the walls of blood vessels become thick and hard, making it difficult for blood to flow freely.

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

“Our ultimate goal with VERVE-101 is to provide a new option to the millions of people with ASCVD around the world, and dosing Phase 1 trial participants for this first indication, HeFH, is an important inflection point to achieve that goal,” said Dr. Andrew Bellinger, Verve’s chief science and medical officer, in a press release.

“Under current standard treatment for HeFH, fewer than 20% of patients reach LDL-C targets due to the limitations of the chronic model, which requires strict patient adherence, regular access to health care and extensive health care infrastructure. VERVE-101 has the potential to change the way cardiovascular disease is treated by keeping LDL-C as low as possible for as long as possible after a single treatment,” he stated in the release.

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

Before launching this clinical trial, 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 an average reduction of more than 60% in LDL-C after 20 months from a non-human primate receiving a single dose of the therapy.

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

“Gene editing could potentially provide a one-time treatment and overcome the problems we face in adhering to chronic treatment of lipids‘ explained Dr Ballantyne.

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 the currently available therapies for lowering cholesterol is that adherence is low,” Dr. Tadwalkar off MNT. “There are several reasons for this, but mainly the standard of care statins, should be taken daily. And there are many people who are not very good at following that routine.

“The nice thing about therapy like this is that it essentially takes the chronic aspect of cholesterol management out of the equation. Compliance is no longer an issue when this kind of therapy works, which is really amazing.

Dr. Rigveda Tadwalkar

When asked about the potential risks of gene editing therapy, Dr. Tadwalkar that while the technology should be safe, there are some concerns that need to be considered.

“The concern is that if an off-target base gets edited and renders another and potentially important gene non-functional, or worse causes another horrible anomaly, it could theoretically be really devastating,” he explained. “While this shouldn’t happen, the specific effects of a therapy in a human can often be different from those in other organisms, so we can’t simply extrapolate from information we have from other organisms. There is also an aspect of irreversibility that must be taken into account.”

“I really feel that if it works as intended it shouldn’t be a big deal as we’ve seen with others PCSK9-based therapies‘ added Dr. Tadwalkar to it. “When we remove this protein, people usually do really well, and we have great long-term results.”

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 is over.

“Phase 1 trials are very small and can’t tell us much about safety – this issue requires much larger and longer studies,” he added.

New CRISPR treatment is being tested on humans

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