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Gene Editing Explained

Verve is harnessing advances in gene editing to develop single-course medicines to treat cardiovascular disease.

Understanding the Human Genome

DNA sequencingAs humans, our DNA consists of a unique code that forms the building blocks for who each of us is as a person – defining key traits, including our health status. 

Our DNA comprises four types of bases, referred to by specific letters, that spell out our unique genetic code. The four bases are adenine (A), cytosine (C), guanine (G) and thymine (T). These bases are present in our DNA as pairs.

Though our genome comprises more than 6 billion base pairs, a single misspelling in that code, known as a point mutation, can serve as the catalyst for serious illness. Through recent genetic discoveries, companies today are leveraging gene editing technologies to address these mutations and potentially cure the underlying cause of disease.

What is Gene Editing?

Gene editing has demonstrated incredible potential in driving new therapeutic breakthroughs to treat disease and continues to evolve. Gene editing works by making a permanent change in a target gene, disrupting the production of certain proteins that cause an underlying disease. Two common forms of gene editing are CRISPR-Cas9 and base editing. 

Base Editing Animation

CRISPR-Cas9 is the most prevalent form of gene editing technology today. Often called “genetic scissors,” CRISPR-Cas9 leverages a guide RNA (gRNA) to steer the Cas9 enzyme to the desired target DNA sequence where the mutation is located. It then activates the enzyme (the scissors) to “cut,” thus initiating the edit. This approach has limitations because it creates a double-stranded break in DNA and relies on cellular mechanisms to complete the editing process. CRISPR-Cas9 therapies can be effective, but they lack full control of the editing outcome, which can result in unwanted DNA modifications. 

Newer gene editing approaches – such as base editing – can potentially address these limitations. 

What is Base Editing?

gene editingBase editing is a next-generation form of gene editing. Base editors can most simply be compared to pencils, in their ability to "erase" and rewrite a specific letter in a gene. 

Base editing medicines comprise a messenger RNA (mRNA) and a gRNA, packaged in a delivery system – most often a lipid nanoparticle (LNP). The process works by binding a modified Cas9 protein to a gRNA, enabling direct targeting of a specific DNA sequence. Base editors are differentiated by the type of base editing enzyme – referred to as a deaminase – which carries out the chemical modification and is fused to Cas9. 

 

Human

A Case Study: Base Editing for Cardiovascular Disease

Editing the PCSK9 Gene

Loss of function of the PCSK9 gene has been associated with low levels of blood LDL-C. VERVE-101 leverages base editing technology to make a single A-to-G spelling change at a specific site in the PCSK9 gene. This edit is intended to switch off the PCSK9 gene, disrupting  PCSK9 protein production by the liver and ultimately lowering LDL-C levels in the blood.

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A SILENT THREAT

Extended exposure to high blood LDL-C  leads to clogged arteries in the heart, resulting in ASCVD.

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HELP IS ON THE WAY

We deliver our product candidate, VERVE-101, via an intravenous infusion into the arm.

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ESTABLISHING HOME BASE

VERVE-101 gets taken up into cells in the liver.

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RNA GETS TO WORK

The mRNA and gRNA are ultimately released inside the liver cells.

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CELLULAR ROAD MAP

The mRNA is translated into the base editing protein, ABE, which binds to the gRNA, and together they travel to the nucleus.

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MAKING THE EDIT

Within the nucleus, the complex scans the DNA using the gRNA to find the target gene PCSK9 and makes a specific A-to-G spelling change within the gene.

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LASTING CHANGE

The single spelling change in the DNA sequence is designed to permanently turn off the PCSK9 gene.

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A HEART-HEALTHY FUTURE

Turning off the PCSK9 gene has the potential to lower blood LDL-C throughout the patient’s life, and thus treat ASCVD.