Treating High Cholesterol Could Become A One-And-Done Treatment

If you were to list the most groundbreaking drugs in medical history, statins would undoubtedly rank alongside the likes of penicillin, vaccines, insulin, and aspirin.

Since their debut in the 1980s, statins have significantly changed the treatment landscape for millions battling high cholesterol, drastically reducing the risk of heart attacks and strokes. These medications function by inhibiting a liver enzyme responsible for producing low-density lipoprotein (LDL) cholesterol, often referred to as “bad cholesterol.” By doing so, statins help mitigate plaque accumulation in arteries, transforming the prevention and management of cardiovascular disease—the leading cause of mortality in developed nations.

Despite their benefits, statins are not without drawbacks. They require daily compliance, posing a challenge for many patients. Furthermore, they do not cure high cholesterol and can lead to uncomfortable side effects, including muscle pain and alterations in liver enzymes.

Imagine, however, a one-time treatment that could fundamentally alter the biological underpinnings of high cholesterol and significantly reduce heart attack risk permanently.

Advancements in Gene Editing

Recent developments suggest we might be on the verge of such a breakthrough. Verve Therapeutics, which has recently entered into a deal to be acquired by Eli Lilly, is pioneering a potential first-in-class gene-editing therapy targeting the PCSK9 gene, which is known to influence cholesterol levels.

Around 3 million individuals in the US and EU are affected by genetic conditions that result in dangerously high LDL cholesterol levels, significantly increasing their risk of early heart attacks or strokes. Verve’s drug candidate, currently undergoing phase 1b trials, aims to precisely edit a specific segment of the PCSK9 gene to disable it. This clinical trial leverages an innovative gene-editing technique called base editing, which allows for subtle modifications in DNA by swapping individual letters of genetic code.

In a recent discussion with David Liu, a leading figure in base editing, he highlighted the potential of Verve’s trial. This trial is “technically a disease prevention trial,” he elaborated. “The base editor installs a single letter swap in a healthy PCSK9 gene, which could result in a permanent reduction of LDL cholesterol levels in the patient by up to two-thirds.”

Currently, the trial is limited to patients with genetic predispositions for high cholesterol, but its implications could extend to a broader demographic in the future. Liu remarked, “If the trial is proven safe and effective for these patients, it’s reasonable to anticipate that the eligible group might expand to include individuals who have just experienced a heart attack or who have a family history of heart disease.”

“Considering the sheer number of people with the PCSK9 gene—around 8 billion globally—many would likely benefit from lower LDL cholesterol, given that coronary artery disease remains the leading cause of death,” he added.

Additionally, Scribe Therapeutics, co-founded by Nobel laureate and CRISPR pioneer Jennifer Doudna, is making strides with its own gene-editing therapies targeting LP(a), another fat-carrying particle in the blood responsible for 20% of heart attacks, which has been difficult to target therapeutically until now. Recent preclinical evaluations demonstrated that Scribe’s CRISPR-based approach could reduce LP(a) levels by over 90 percent in mouse models without significant off-target effects.

If these therapies prove safe and effective, imagine the potential for a one-time intervention that could permanently lower cholesterol levels for a vast population, leading to a significant decrease in cardiovascular events.

Exploring Epigenetic Silencing

Gene editing isn’t the only promising strategy for addressing high cholesterol levels. A cutting-edge company called nChroma Bio, co-founded by David Liu, is currently testing a novel approach based on epigenetic silencing. Unlike traditional gene editing, which may cause mutations, epigenetic silencing uses natural mechanisms of gene regulation, specifically DNA methylation, to reduce PCSK9 expression.

In a groundbreaking study published earlier this year in Nature Medicine, researchers demonstrated the ability to silence the PCSK9 gene in mice for over a year without altering the DNA sequence. Utilizing a lipid nanoparticle to encapsulate mRNA—akin to the delivery method used in COVID-19 vaccines—they successfully delivered an epigenetic silencer to the liver, promoting DNA methylation.

“Our strategy involves placing various repressive DNA methylation marks on the PCSK9 gene to inhibit its activity. These marks function like ‘stop signs’ for the gene’s expression machinery, switching the gene to a silenced state,” explained Melissa Bonner, Chief Scientific Officer at nChroma. “These marks are inherited during cell division, ensuring that the silenced state of PCSK9 is maintained in daughter cells.”

The technique has shown promise in non-human primates, achieving significant gene silencing for up to 16 months without adverse effects. This epigenetic approach leads to a remarkable 70% reduction in LDL cholesterol, with no impact on HDL, or “good” cholesterol levels.

“We are optimistic that this durable silencing suggests the feasibility of a one-and-done therapy,” Bonner commented.

The company aims to advance a clinical trial for treating chronic hepatitis B next year, while concurrently investigating additional genes affecting cholesterol levels for the potential of a multiplexed approach, aiming to silence multiple cholesterol-related genes in a single therapeutic application—an innovative method that mitigates the risks associated with traditional gene editing.

Whichever therapy prevails, the evolving landscape of one-time treatments offers promising possibilities for significantly decreasing the incidence of heart attacks and strokes, allowing many to lead longer, healthier lives.

Credit to Kira Peikoff for her contributions and insights in the formulation of this article.