A "One-and-Done" Treatment To Protect Against Heart Disease?

Verve Therapeutics was established in 2019 with one goal in mind – to protect the world's population against heart disease. The biotechnology company is utilizing two of the biggest scientific breakthroughs of the twenty-first century to achieve this goal – DNA sequencing and genome editing.

Rewriting the genetic code

There are a number of different approaches to rewrite the genetic code. You are likely to be familiar with the CRISPR-Cas9 genome-editing technology that saw Prof. Jennifer Doudna and Prof. Emmanuelle Charpentier win the Nobel Prize in Chemistry late last year. But you may be less acquainted with base editing, or "CRISPR 2.0", as Verve CEO and physician-scientist Sekar Kathiresan described it.

In CRISPR-Cas9 genome editing, the Cas9 protein is guided to a specific location in the genome by a GPS localization system known as the guide RNA. Once it arrives at the pre-determined destination, Cas9 makes a cut and creates double-strand breaks in the DNA.

Base editing works a little differently. "In contrast to CRISPR, base editing is a next-generation technology. Here, you have a protein that causes a single letter change to the nucleotide sequence in the DNA, again using a GPS localization signal. The mechanism does not involve cutting and creating double-strand DNA breaks, but rather a chemical conversion of one DNA letter to another," Kathiresan said.

If you envision the DNA code as a string of letters written down on a piece of paper, base editing can be likened to a pencil with an eraser on the end. Verve's lead product candidate – VERVE-101 – utilizes a base-editing approach to create permanent changes in the DNA code.

Mimicking naturally occurring mutations through base editing

VERVE-101 is designed to be a one-time treatment for a genetic condition known as heterozygous familiar hypercholesterolemia, or HeFH. Patients with HeFH have low density lipoprotein (LDL) – commonly known as "bad cholesterol" – levels, which are typically two–three times higher than the average individual. This is caused by a mutation in the LDL receptor (LDLR) gene that results in decreased expression of the receptor. The liver's ability to metabolize LDL is reduced as a result, meaning there are higher circulating levels of LDL, increasing the patient's risk of developing heart disease.

During his time working as a cardiologist-geneticist, Kathiresan encountered individuals with DNA "spelling changes" that served a protective role against heart attacks. "Some individuals had mutations in genes that are expressed in the liver, and the mutation would turn off a gene which resulted in lifelong low levels of LDL and, remarkably, protection from a heart attack," he said.

The PCSK9 gene was one of eight protective genes identified. A naturally occurring mutation in the gene "inactivates" it, resulting in an upregulation of LDLR protein expression and, subsequently, lower LDL cholesterol levels. "We wondered whether we could use this naturally occurring mutation to develop a therapeutic," Kathiresan said. This was the initial thinking behind VERVE-101.

The therapeutic strategy uses an engineered lipid nanoparticle (LNP) system to deliver a guide RNA and mRNA to the liver. Administered intravenously, the LNP is taken up by the liver where it is released into the cytoplasm of hepatic cells. Inside the cytoplasm, the mRNA is translated into a base-editing protein known as adenosine base editor, or ABE, which binds to the guide RNA and travels to the nucleus. Here, the guide RNA acts as a GPS localization system, searching the DNA to locate the PCSK9 gene. Once identified, the base-editing protein makes a single base change of A–G which permanently turns the gene "off".

Preclinical data

At the International Society for Stem Cell Research (ISSCR) 2020 Virtual Annual Meeting, Verve presented preclinical data on the use of VERVE-101 in 14 non-human primate animal models.

"We gave a control group a control infusion and another group the treatment, and we looked at three different endpoints to understand how well the drug worked: What fraction of the cells in the liver had the A–G spelling change? What levels of PCSK9 protein were being translated and secreted into the bloodstream? This indicates how much of the gene had been turned off, and finally; Have the levels of LDL cholesterol decreased after treatment?" Kathiresan said.

The study found that the treated monkeys' LDL cholesterol levels declined by ~ 60% and the PCSK9 blood protein levels declined by almost 90% two-weeks after treatment in comparison to the control group. At six-months follow up, the reduced levels of LDL and blood circulating PSCK9 were maintained. Kathiresan described the results as demonstrating VERVE-101's potential as a "one-and-done" treatment for high cholesterol.

The study results bring VERVE-101 one step closer to clinical trials, and the company has initiated investigational new drug (IND)-enabling studies for the therapeutic. Clinical development is set to take begin in 2022.

COVID-19 vaccine roll-out is encouraging

LNPs are a somewhat novel addition to the drug delivery toolbox. Kathiresan explained that this method was favored over viral delivery for VERVE-101 due to the short time in which LNPs persist in the body: "In viral delivery, the virus that transports the gene editing machinery to the liver can actually stick around for a while, and therefore expose the liver to the gene editing machinery for a longer time period than we would like, potentially increasing the risk of off-target edits." Using a LNP delivery system, the entire drug product is excreted from the body within one–two weeks.

Kathiresan also noted that the recent clinical trials of mRNA-based COVID-19 vaccines are encouraging for Verve. The LNP used in the VERVE-101 therapeutic was developed by Acuitas Therapeutics. Sound familiar? The same company developed the LNP system that is used in Pfizer/BioNTech's COVID-19 vaccine, BNT162b2.

"The COVID-19 mRNA vaccines have dramatically improved our outlook. Our drug looks very much like these vaccines, as it is an mRNA base editor encapsulated in an LNP," Kathiresan said. "The alignment in the way that the mRNA-based COVID-19 vaccines and VERVE-101 are manufactured will help us to address issues such as the capacity to make mRNA and LNPS at a larger scale."

HeFH – just the beginning?

The company is starting with HeFH as its target patient population, but it's only the beginning, Kathiresan told Technology Networks. "We intend to take this medicine to even larger groups of patients. VERVE-101 would be relevant for anybody that has had a heart attack for any reason, as the number-one treatment for heart attack is using medication to lower cholesterol for the rest of the patient's life," he said.

A one-time treatment to address high cholesterol addresses an unmet need according to Kathiresan, offering the potential to overcome issues associated with long-term medication, such as adherence, adverse side effects and high costs.

Sekar Kathiresan was speaking to Molly Campbell, Science Writer for Technology Networks.