Although still under investigation, this advance offers a potential new strategy for cardiovascular disease prevention and the treatment of patients with severe hypercholesterolaemia. The therapy acts directly at the genetic level, primarily in hepatocytes, which play a central role in cholesterol regulation. Known as VERVE-102, it is designed to be as effective in a single administration as the current treatment which requires lifelong chronic medication or repeated injections.
Hypercholesterolaemia is one of the major risk factors for cardiovascular disease. Elevated cholesterol levels are typically asymptomatic but, over time, can promote lipid accumulation within arterial walls, increasing the risk of myocardial infarction, stroke and peripheral vascular disease.
What is LDL cholesterol?
Low-density lipoproteins, commonly referred to as LDL cholesterol, are one of the principal carriers of cholesterol in the bloodstream, together with high-density lipoproteins (HDL) and other triglyceride-rich lipoproteins. LDL cholesterol is often termed “bad cholesterol” because persistently elevated levels can lead to its deposition within the arterial wall.
These deposits can give rise to atherosclerotic plaques, accumulations of cholesterol and other substances within the arterial wall. Over time, they may narrow and stiffen the arteries, a process known as atherosclerosis, and increase the risk of myocardial infarction, stroke and circulatory disorders.
Cholesterol is essential for the body, but its levels should be maintained within the target ranges established for each individual according to their cardiovascular risk. The same LDL cholesterol level may have different implications depending on age, risk factors and the presence or absence of cardiovascular disease.
How does the new therapy work?
The therapy targets the PCSK9 gene, which provides the instructions for the liver to produce the PCSK9 protein, whose function is related to the uptake of LDL cholesterol. When levels of this protein increase, the liver becomes less able to remove LDL cholesterol from the bloodstream. Some individuals carry genetic variants in this gene that make it particularly active. As a result, they produce large amounts of PCSK9 protein, and the liver loses part of its ability to eliminate LDL cholesterol. These individuals have very high blood cholesterol levels and develop one of the genetic forms of the disease known as familial hypercholesterolaemia.
VERVE-102 is designed to "switch off" this gene in liver cells by using lipid nanoparticles, which are small fat particles that deliver RNA to the liver. Once inside the cells, this RNA guides the editing system to the specific site to be modified in the DNA. The technology used is known as base editing because it modifies one of the bases that make up the DNA sequence. It can be understood as a highly precise correction of a single letter in the genetic code. Rather than cutting the DNA, the system replaces one letter with another, causing the PCSK9 gene to stop functioning.
When the DNA associated with the PCSK9 protein is modified, the amount of protein produced decreases significantly and, as a result, the liver can remove more LDL cholesterol from the bloodstream.
Why is it considered a paradigm shift?
This treatment is considered a potential paradigm shift because it proposes a single intervention to replace continuous treatment. Most current cholesterol-lowering therapies are taken or administered repeatedly to maintain their protective effect.
Statins, for example, are the most widely used treatment and have been shown to reduce the risk of myocardial infarction and stroke. Other therapies are also available, including ezetimibe, bempedoic acid and periodic injections that block the PCSK9 protein in the bloodstream or reduce its production. These treatments can be highly effective, but require continuous administration.
This highlights one of the major challenges in cholesterol management: treatment adherence. As many as 50% of individuals discontinue their medication during the first year. Because elevated cholesterol levels are usually asymptomatic, some people stop treatment when they feel well or perceive no immediate benefit.
A therapy capable of maintaining its effect following a single infusion could help overcome this problem. However, it must be demonstrated that this benefit is sustained over the long term and that the treatment is safe in larger population groups.
An effect inspired by a natural protective mechanism
The therapeutic target, the PCSK9 gene, is of particular interest because some individuals are born with genetic variants that cause this protein to function poorly or not at all. These individuals typically have very low LDL cholesterol levels and a lower cardiovascular risk. This is precisely the opposite situation to the aforementioned individuals with familial hypercholesterolaemia.
The new therapy seeks to reproduce this protective effect. However, rather than temporarily blocking the protein, it aims to modify the gene that controls its production. If the genetic modification is maintained over time, the effect could last for years, although this possibility still needs to be confirmed through longer-term follow-up studies.
What results have been observed?
The initial results came from a phase 1b clinical trial involving 35 participants. At this stage, the primary objectives were to evaluate treatment safety and try to establish the most effective dose.
The most significant finding was the reduction of LDL cholesterol by more than 60% at the highest dose evaluated, with this effect being maintained for at least 12 months. This reduction is particularly significant because LDL is one of the main therapeutic targets in cardiovascular disease prevention.
The results also indicate that the effect is dose-dependent: higher doses produce greater reductions in cholesterol levels. This suggests that the greater the number of liver cells that are edited, the greater the impact on LDL levels.
Another important aspect is the durability of the effect. Liver cells undergo natural renewal, yet the reduction in cholesterol persists beyond this initial period. This supports the hypothesis that the genetic modification may be maintained over time and could even be passed on from an edited cell to its daughter cells during liver cell division.
When could this treatment be available?
The timeline for general availability depends on the results of the clinical trials currently underway: the current study began in 2024 and is scheduled to continue until 2027.
Because the treatment modifies DNA, subsequent larger trials would be required to confirm robust safety and efficacy, as well as the patient profiles most likely to benefit, before this therapy could be incorporated into clinical practice.
The therapy has received fast track designation from the US regulatory agency, which may accelerate its evaluation if results continue to be favourable. Nevertheless, several years are likely to pass before a potential approval for widespread use could be considered.
At present, cholesterol management continues to be based on individual cardiovascular risk assessment, the maintenance of healthy lifestyle habits and the use of pharmacological treatment when indicated. The new therapy represents a potential future option for individuals at high cardiovascular risk or with genetic forms of hypercholesterolaemia that are difficult to control.
A promising advance, but still under investigation
Preliminary results indicate that a single infusion could produce sustained reductions in LDL cholesterol levels in individuals at high cardiovascular risk. However, its efficacy and safety still need to be confirmed in larger clinical trials with longer follow-up periods.
In the meantime, cholesterol management continues to be based on early detection, individual cardiovascular risk assessment, healthy lifestyle habits and the use of available treatments when indicated.
INFORMATION DOCUMENTED BY:
Dr Emilio Ortega, Department of Endocrinology and Nutrition, Hospital Clínic Barcelona
