CRISPR Gene Therapies Offer New Hope Against High Cholesterol
Innovative CRISPR gene therapies are showing remarkable potential in tackling chronically high cholesterol levels, offering a significant reduction in the risk of cardiovascular disease. Early results from Scribe Therapeutics, presented at the American Heart Association Scientific Sessions 2025, demonstrate a dramatic decrease in harmful lipid levels.
Breakthrough Results in Animal Models
Scribe Therapeutics has unveiled three CRISPR formulations designed to combat high cholesterol and other lipid-related heart disease risks. In preclinical studies involving lab-grown cells, mice, and non-human primates, these therapies achieved significant reductions in dangerous fats.
The flagship formulation, utilizing epigenome editing, successfully lowered “bad cholesterol” (LDL) levels in primates for an extended period of over 515 days following a single injection. This approach modifies gene expression without altering the underlying DNA sequence, potentially offering a safer profile than traditional gene editing.
Two other formulations targeted lipoprotein(a) and triglycerides, both implicated in the buildup of arterial plaques. In mice, these treatments resulted in a reduction of these fatty substances by over 95 percent in early trials.
Addressing a Global Health Crisis
High cholesterol, particularly elevated LDL levels, is a major contributor to cardiovascular disease worldwide, leading to heart attacks, strokes, and other serious conditions. Current management often relies on lifelong medication like statins and dietary changes, which can be challenging for patients to adhere to consistently.
The gene PCSK9 has been identified as a key player in regulating LDL cholesterol. While drugs targeting the PCSK9 protein have shown efficacy, directly inhibiting the gene or its activity offers the potential for a more durable solution. Previous studies, including a small human trial in 2023, have shown promising results with CRISPR-based approaches to correct genetic predispositions for high cholesterol.
Epigenetic Editing: A Safer Frontier
Epigenetic editing represents a promising advancement, offering a way to control gene activity without making permanent changes to the genome. This method targets the molecular mechanisms that switch genes on or off, potentially mitigating the risks associated with direct DNA alteration. Scribe’s approach uses CRISPR-CasX to create an epigenetic silencer that suppresses PCSK9 activity.
In non-human primates, this epigenetic silencer reduced LDL levels by up to 68 percent. Crucially, the effect persisted for over 515 days, and the treatment showed high specificity, with no notable changes in the activity of other genes in cultured human liver cells. This suggests a potential for a new class of durable epigenetic medicines.
Targeting Multiple Lipid Drivers
Beyond PCSK9, CRISPR technology is being explored to address other genetic factors contributing to cardiovascular disease. CRISPR Therapeutics, in collaboration with the Cleveland Clinic Foundation, has investigated disabling the ANGPTL3 gene, which is linked to lower LDL levels and reduced heart disease risk in individuals with natural genetic variations.
A Phase 1 clinical trial involving 15 participants with lipid disorders showed that a single administration of a CRISPR-Cas9 therapy targeting ANGPTL3 led to significant and sustained reductions in ANGPTL3 protein and LDL levels for at least 60 days, with the treatment being well-tolerated. Researchers believe this “one-and-done” approach could revolutionize the management of lifelong lipid disorders.
Combating Lipoprotein(a) and Triglycerides
Lipoprotein(a) [Lp(a)] is another significant cardiovascular risk factor, affecting an estimated 30 percent of the global population. Elevated Lp(a) levels are largely genetic and difficult to manage with conventional methods. Scribe’s CasXE gene editor has demonstrated the ability to inactivate the gene responsible for producing Lp(a) in liver cells, leading to up to a 95 percent reduction in fatty balls in mice without detectable off-target effects.
Furthermore, a different CasXE editor developed by Scribe targets the APOC3 gene, which is associated with lipid production. In preclinical studies, a single injection modified over 75 percent of liver cells in monkeys and virtually eliminated high blood lipid levels in mice. These preliminary findings suggest that CRISPR-based therapies could offer a paradigm shift, potentially replacing decades of daily medication with a single, effective treatment.
This story was based on reporting from SingularityHub. Read the full report here.
