A team of researchers from the biotech Chroma has used epigenetic editing to silence PCSK9 as a possible durable, one-time treatment for high cholesterol. Silencing was effective for at least one year in mice. This team 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. In cynomolgus monkeys, a single administration of the epigenetic editor potently and durably decreased circulating PCSK9 protein levels by approximately 90% with a concomitant reduction in low-density lipoprotein cholesterol levels by approximately 70%.
Their work was published in Nature Medicine, and the lead author is Frederic Tremblay, PhD, of Chroma Medicine, Boston.
High cholesterol is a major risk factor for heart disease, which is a leading cause of death worldwide. In the United States alone, one person dies every 33 seconds from cardiovascular disease. In 2022, 702,880 people died from heart disease, according to the U.S. Centers for Disease Control (CDC).
The PCSK9 protein plays a critical role in regulating cholesterol levels by breaking down LDL receptors, which clear “bad” cholesterol from the bloodstream. Current treatments, such as monoclonal antibodies and ribonucleic acid (RNA)-based treatments, lower PCSK9 activity but require continuous administration. Gene editing such as clustered, regularly interspaced short palindromic repeats (CRISPR) have shown promise, but they involve permanent deoxyribonucleic acid (DNA) changes, raising safety concerns.
In this study, durable silencing using programmable epigenetic editors (EEs) was carried out in human cells in vitro, further, gene silencing was maintained for many months. The epigenetic editors used comprised a combination of DNA methyltransferase and KRAB-based transcriptional repressor domains fused to a DNA-binding domain either as single or multiple fusion proteins.
The authors write, “Inducing DNA methylation at CpG dinucleotide sites located at promoter regions has proven to be effective in durably locking genes in a silenced state. DNA methylation is a repressive mark that is durable and faithfully propagated through cell division by the activity of the DNA methyltransferase DNMT1.”
Further, they note, “Unlike gene editing methods that rely on a single-strand DNA break (nick), such as base and prime editing, or a double-strand DNA break (cut), such as CRISPR–Cas9 nuclease editing, targeted epigenetic editing does not disrupt the integrity of the DNA sequence, thus avoiding potential genotoxic risks associated with nuclease editing and with much lower frequency, base and prime editing.”
In addition, this team showed they could reverse the epigenetic editing in mice with previously silenced PCSK9 upon treatment with a targeted epigenetic activator designed to demethylate the PCSK9 locus
