GEO series

Development of a potent epigenetic editor targeting human PCSK9 with durable reduction of cholesterol in mice and non-human primates [hybrid capture methylseq]

GSE282436 Homo sapiens; Mus musculus Genome binding/occupancy profiling by high throughput sequencing 66 samples Submitted 2025/02/05 Platform GPL16417Platform GPL15520

Summary

DNA methylation in gene promoter regions is a conserved, innate epigenetic mechanism to control gene expression. Transient application of epigenetic editors designed to induce DNA methylation has been shown to silence genes in cultured cells and in mice. Here we report the development of a potent, efficacious, and specific human PCSK9-targeting epigenetic editor. A single administration of lipid nanoparticles encapsulating mRNA encoding the epigenetic editor which precisely targets the PCSK9 locus was sufficient to drive near-complete silencing in transgenic mice expressing human PCSK9. Silencing was durable for at least one year and was fully maintained following partial hepatectomy-induced liver regeneration. In addition, we showed reversibility of epigenetic editing in previously silenced mice upon treatment with a targeted epigenetic activator designed to demethylate the PCSK9 locus. Importantly, a single administration of the epigenetic editor robustly, potently, and durably decreased circulating PCSK9 (~90%) in cynomolgus monkeys with concomitant reduction in low-density lipoprotein cholesterol (~70%). These findings support the development of an epigenetic editor targeting PCSK9 for the treatment of hypercholesterolemia and demonstrate the broad therapeutic potential of precise, efficacious, durable, and reversible epigenetic editing in vivo

Published in

A potent epigenetic editor targeting human PCSK9 for durable reduction of low-density lipoprotein cholesterol levels

Tremblay F, Xiong Q, Shah SS et al. · Nature medicine 2025 · PMID 39930141 · doi:10.1038/s41591-025-03508-x

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Direct links to NCBI, no account and no request form: the whole study as GSE282436_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 66 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1188579 and SRA study SRP546520. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 39930141) ↗

Study design

10 conditions, mostly with about 4 replicates each

hPCSK9 tg mouse liver, PCSK9-EE, day365, ×6 hPCSK9 tg mouse liver, Vehicle, day28, ×4 hPCSK9 tg mouse liver, WTCas9, day28, ×4 hPCSK9 tg mouse liver, CRISPRi, day28, ×4 hPCSK9 tg mouse liver, PCSK9-EE, day28, ×4 hPCSK9 tg mouse liver, Cas9, Resected, ×4 hPCSK9 tg mouse liver, Cas9, Sham, ×4 hPCSK9 tg mouse liver, Vehicle, Resected, ×3 +3 more

Supports a between-group comparison across 39 samples.

10 replicated groups read from the first 40 of 66 sample titles; they account for 39 of them. Check it against the sample list below before relying on it.

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