Next-Gen Atherosclerosis Treatments Target Inflammation at Its Source

Atherosclerosis remains the leading cause of death globally despite decades of effective lipid-lowering therapy. This 2025 review from Oxford and NYU argues that the field must transition from population-level risk factor management to next-generation, mechanism-driven interventions capable of reversing established disease — not merely slowing its progression.

The authors first survey advances in LDL reduction, noting that CRISPR base editing delivered via lipid nanoparticles achieved ~90% knockdown of PCSK9 in a single infusion, with LDL reductions sustained for at least 8 months in early human trials. Epigenetic silencing of PCSK9 using zinc-finger proteins offers a complementary approach without DNA strand breaks, with effects persisting even after forced liver regeneration in mice. For lipoprotein(a), phase 3 siRNA trials (HORIZON and OCEAN-a) are underway, and an oral Lp(a) inhibitor has entered early-phase testing.

On the inflammation front, colchicine demonstrated cardiovascular benefit in COLCOT and LoDoCo2 trials (HRs of 0.77 and 0.69 respectively), though the OASIS-9/CLEAR SYNERGY acute MI trial showed no benefit, raising questions about patient selection and timing. The review contextualizes these findings within a broader argument: systemic inflammatory load — reflected by hsCRP — may be a stronger residual risk predictor than LDL in well-treated patients, pointing to inflammation pathways as the next major therapeutic frontier.

A particularly novel emphasis is placed on bone marrow biology. Clonal hematopoiesis of indeterminate potential (CHIP), especially mutations in TET2 and DNMT3A, is presented as causally linked to amplified myeloid inflammation and accelerated atherosclerosis. Trained immunity — whereby innate immune cells acquire an epigenetically encoded hyperinflammatory memory following prior insults such as myocardial infarction — is identified as a systems-level driver that extends inflammation far beyond the plaque itself. The authors propose that targeting these upstream, bone-marrow-level processes could fundamentally alter cardiovascular risk.

The review is candid about a central limitation: unlike cancer, atherosclerotic plaques are inaccessible, making it extremely difficult to characterize individual patients' disease processes and select those most likely to benefit from targeted therapies. The authors call for advances in circulating biomarkers, single-cell sequencing of peripheral blood cells, and AI-driven predictive models to bridge this gap. Despite the promise of the technologies described, clinical translation will require solving the patient-stratification problem before precision immunotherapy for atherosclerosis becomes reality.