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

ABSTRACT: 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

ORGANISM(S): Macaca fascicularis

PROVIDER: GSE282432 | GEO | 2025/02/05

REPOSITORIES: GEO

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Project description:Background: Hepatic knockdown of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene or the angiopoietin-like 3 (ANGPTL3) gene has been demonstrated to reduce blood low-density lipoprotein cholesterol (LDL-C) levels, and hepatic knockdown of the angiotensinogen (AGT) gene has been demonstrated to reduce blood pressure. Genome editing can productively target each of these three genes in hepatocytes in the liver, offering the possibility of durable “one-and-done” therapies for hypercholesterolemia and hypertension. However, concerns around making permanent gene sequence changes via DNA strand breaks might hinder acceptance of these therapies. Epigenome editing offers an alternative approach to gene inactivation, via silencing of gene expression by methylation of the promoter region, but the long-term durability of epigenome editing remains to be established. Objectives and Results: We assessed the ability of epigenome editing to durably reduce the expression of the human PCSK9, ANGPTL3, and AGT genes in HuH-7 hepatoma cells. Cells treated with the CRISPRoff epigenome editor and PCSK9 guide RNAs were maintained for up to 124 cell doublings and demonstrated durable knockdown of gene expression and increased CpG dinucleotide methylation in the promoter, exon 1, and intron 1 regions. In contrast, cells treated with CRISPRoff and ANGPTL3 guide RNAs experienced only transient knockdown of gene expression. Cells treated with CRISPRoff and AGT guide RNAs also experienced transient knockdown of gene expression; although initially there was increased CpG methylation throughout the early part of the gene, this methylation was geographically heterogeneous—transient in the promoter, and stable in intron 1.Conclusions: This work demonstrates precise and durable gene regulation via methylation, supporting a new therapeutic approach for protection against cardiovascular disease via knockdown of genes such as PCSK9. However, the durability of knockdown with methylation changes is not generalizable across target genes, likely limiting the therapeutic potential of epigenome editing compared to other modalities.

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

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