Investors are excited and terrified of humanity's emerging ability to edit our own genomes. That helps to frame why shares of Verve Therapeutics lost over one-third of their value when the development-stage biopharma paused a clinical trial after serious side effects were observed.

However, the specific side effects observed and the nerdy details of the gene being silenced strongly suggest the adverse events weren't related to mucking around with genes. Instead, they were likely related to the type of lipid nanoparticle (LNP) used to deliver the base editing payload to liver cells and the body's initial reaction to silencing the gene itself. That bodes well for VERVE-102, which is delivered inside a refined LNP chemistry more likely to avoid the side effects of its predecessor. Investors will soon find out: a preliminary phase 1 data readout is expected in the first half of 2025.

VERVE-102 is a CRISPR base editing candidate designed to silence the PCSK9 gene, which plays a role in regulating LDL-cholesterol (LDL-C). The asset utilizes an engineered adenine base editor that changes the letters of the genetic alphabet to alter gene function. Adenine base editors can change A to T and G to C. If the 1997 movie GATTACA came into contact with an adenine base editor, then the title might instead have read CTTTTCT. Oops.

This specific drug candidate only changes a single base pair ("letter") in the PCSK9 gene. That's sufficient to silence its expression, which can permanently lower an individual's LDL-C levels. Will it be safe to permanently silence this gene?

The discovery of the PCSK9 gene's role in regulating LDL-C was aided by the discovery of rare mutations in the human population. People from various ethnicities have naturally-occurring mutations that offer protection from high cholesterol. They can eat whatever they want and are never at risk of high LDL-C. Lucky bastards. Intriguingly, the mutation is almost non-existent in people of European ancestry, but more common in African, Indian, and Middle Eastern populations. It's a good reminder of the blind spots lurking in global genetic databases, which typically only include samples from individuals of European descent.

There are also FDA-approved drug products that inhibit the PCSK9 enzyme (small molecules and antibodies) or silence the PCSK9 gene (RNAi), including an RNAi drug product called Leqvio. They're effective and safe, so we know this is a clinically-validated target – even with genetic medicines.

Although VERVE-102 is initially being studied in a relatively rare disease, the long-term goal is to evaluate its potential to reduce the risk of cardiovascular disease in the general population. Imagine getting an infusion once (or several times over your lifetime) and then enjoying healthy levels of cholesterol regardless of your diet. Check back in the early 2030s for results.