ArticleNature medicine2025
A potent epigenetic editor targeting human PCSK9 for durable reduction of low-density lipoprotein cholesterol levels.
Article in Nature medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed.
- Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates.Nature biotechnology · 2026Article
- PCSK9 alleviates doxorubicin‑induced pyroptosis of cardiomyocytes.Molecular medicine reports · 2026Article
- Durable epigenetic silencing with a TALE-based editor.Nature biotechnology · 2026Article
- On-target and off-target activities of CRISPR therapeutics across scales.Trends in biotechnology · 2026Review
- Targeting mNature communications · 2026Article
- Unmet Cardiovascular Risk Beyond LDL-C: A Perspective on Managing Residual Cardiovascular Risk.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Lipid lowering in coronary artery disease - not just statins.Clinical medicine (London, England) · 2026Review
- Base editing and silencing of PCSK9 shows clinical promise in humans.Nature reviews. Cardiology · 2026Article
- Article
- Epigenetic editing makes its mark.Nature · 2026Article
- Cytosine base editing of LPA in transgenic mice averts large deletions.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Rewriting the epigenome: CRISPR tools for biological discovery and therapeutics.Current opinion in biomedical engineering · 2026Article
- Next generation technologies for CRISPR-based epigenome and transcriptional modulation.Current opinion in biomedical engineering · 2026Article
- Clinical translation of epigenome editing technologies.Current opinion in biomedical engineering · 2026Article
- Optimized lentivirus-derived virus-like particles for efficient delivery of Cas9-based genome editors.Nucleic acids research · 2026Article
- Gene Therapy for Cardiovascular and Cerebrovascular Disease: Mechanisms, Translational Barriers, and the Road Ahead.Biomedicines · 2026Review
- Simultaneous orthogonal cell engineering by a single CRISPR-Cas9 polyfunctional editor.Nature communications · 2026Article
- Recent Developments in Lipid Nanoparticle-Mediated Delivery of Biotherapeutics and Gene Therapy Across the Blood-Brain Barrier.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- CRISPR Interference to Inhibit Oncogenes for Cancer Therapy.International journal of molecular sciences · 2026Review
- mRNA medicine for cardiovascular disease.Nature cardiovascular research · 2026Review
Corrections and comments
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Authors and funding
28 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Epigenetic editing holds the promise of durable therapeutic effects by silencing disease-causing genes without changing the underlying DNA sequence. In this study, we designed an epigenetic editor to target human PCSK9 and thereby induce DNA methylation at this locus. A single administration of lipid nanoparticles encapsulating mRNA encoding this epigenetic editor was sufficient to drive near-complete silencing of human PCSK9 in transgenic mice. Silencing was durable for at least 1 year and was fully maintained after partial hepatectomy-induced liver regeneration. In addition, we showed reversibility of epigenetic editing in mice with previously silenced PCSK9 upon treatment with a targeted epigenetic activator designed to demethylate the PCSK9 locus. Notably, in cynomolgus monkeys, a single administration of the epigenetic editor potently and durably decreased circulating PCSK9 protein levels by approximately 90% with concomitant reduction in low-density lipoprotein cholesterol levels by approximately 70%. These findings demonstrate the therapeutic potential of durable and reversible epigenetic editing in vivo and support the development of epigenetic editor-based treatment for hypercholesterolemia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.