CRISPRoff suppresses liver gene expression, improving blood lipids and atherosclerotic lesions in mice
Background: Seeking longer-lasting lipid control
CRISPRoff, which suppresses the expression of specific genes in the liver, lowered blood lipids and improved indicators associated with atherosclerotic lesions in mice. Published in Journal of Genetics and Genomics, this proof-of-principle study demonstrated the potential of epigenome editing, which does not alter the DNA sequence, in animal experiments.
Hypercholesterolemia is a major factor promoting atherosclerosis. Existing lipid-lowering treatments substantially improve blood lipid levels, but the researchers sought a more durable, safe, and efficient control strategy. Their approach was epigenome editing intended to maintain suppression of disease-related gene expression while leaving the DNA sequence intact.
Key findings: Lower blood lipids in two mouse models
The researchers delivered the CRISPRoff platform using adeno-associated virus (AAV) or lipid nanoparticles (LNPs) to suppress the expression of Hmgcr or Pcsk9 in the liver in vivo. The technology regulates the expression of specific genes; it should not be interpreted as shutting down the overall function of liver cells.
The experiments used C57BL/6J wild-type mice and ApoE-deficient mice. Strong, sustained suppression of target gene expression was observed in both models, and the researchers reported reductions in blood total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides. These measurements reflect blood lipids, not a reduction in body fat.
In ApoE-deficient mice, suppressing Pcsk9 also produced changes associated with atherosclerotic lesions. Lipid accumulation in the liver and aortic root decreased, as did necrotic core formation within lesions and macrophage infiltration. Improved plaque stability was also reported. These results indicate improvements in several lesion characteristics alongside blood lipid levels. However, the abstract presented these lesion-related findings only for Pcsk9 suppression in ApoE-deficient mice.
Implications and outlook: Preclinical findings requiring further assessment of durability and safety
The results show that epigenetic suppression of target genes in the liver can lead to improved lipid control and atherosclerotic lesions in mice. The researchers interpreted the findings as proof of principle for an approach to stably suppress cardiovascular disease-related targets. The provided abstract does not report a direct comparison showing greater efficacy than existing drugs.
The available material is an abstract, so effect sizes, observation period, sample size, number of administrations, dose, and detailed safety results cannot be verified. The report of “sustained suppression” alone does not establish a permanent effect or an effect achieved with a single administration. This mouse study cannot determine whether the approach reduces cardiovascular events in people or could replace existing treatments. Further development should specifically assess how long suppression lasts, administration conditions, and safety.
Source: Bibliographic record and abstract indexed in Europe PMC.
Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with hypercholesterolemia serving as a critical driver of atherogenesis. Although current lipid-lowering therapies substantially improve circulating lipid profiles, strategies that provide more durable, safe, and efficient control of lipid metabolism are still needed. Epigenome editing offers a promising approach for long-lasting repression of disease-modifying genes without altering the underlying DNA sequence. Here, we develop CRISPRoff platforms delivered by adeno-associated virus or lipid nanoparticle to epigenetically silence hepatic Hmgcr or Pcsk9 in vivo. In both C57BL/6J wild-type and ApoE
Researchers developing candidate strategies for lipid control can use these findings to design preclinical experiments that jointly assess suppression of target genes in the liver, changes in blood lipids, and changes in atherosclerotic lesions. In particular, the Pcsk9 suppression results in ApoE-deficient mice provide a basis for examining the relationship between lower blood lipids and improved lesion characteristics. Development will need to establish how long suppression lasts, the administration conditions, and safety. To develop this approach into a treatment for patients, efficacy and safety must also be assessed in people; the current findings provide animal-study evidence supporting that development direction.