New oligonucleotide therapy offers hope for liver disease cure

Groundbreaking research from Montreal University has identified the chaperone protein PCSK7 as an exciting new therapeutic target for Non-alcoholic fatty liver disease (NAFLD)

Scientists may have found a way to treat a fast-growing form of liver disease using oligonucleotide gene therapy.

Montreal University researchers discovered that using an antisense oligonucleotide (ASO) to ‘silence’ the activity of the PCSK7 protein reversed the symptoms of Non-alcoholic fatty liver disease (NAFLD) in mice.

The new findings could represent a significant step towards finding a cure for NAFLD – which can lead to life-threatening liver conditions, and already affects around 30% of people in Western nations. In one in five cases, early stage NAFLD leads to cirrhosis, which may in turn require a liver transplant.

The Montreal team chose its therapeutic target after observing associations between PCSK7 genetic variations and disruptions in lipid metabolism linked to NAFLD – although the precise molecular mechanisms underlying this connection were unclear.

But in this groundbreaking research, the Canadian team demonstrated that the PCSK7 gene encodes a chaperone protein, also called PCSK7, which plays a pivotal role in regulating apoB, the primary protein constituent of low-density lipoprotein (LDL) cholesterol particles.

The research not only established PCSK7’s role in promoting NAFLD by binding apoB and regulating its secretion – but also demonstrated that removal of PCSK7 in liver cells led to 50% degradation of apoB.

To validate their findings, the group used a high fat, fructose and cholesterol diet to induce NAFLD in two groups of laboratory mice – ‘wild type’ (WT) animals with PCKS7, and Pcsk7−/− mice who were genetically engineered to lack the protein.

The animals were then placed on a different diet to allow them to recover for four weeks, but the Pcsk7−/− mice “recovered more effectively than WT mice from all NAFLD-related liver phenotypes.”

“Mechanistically, the loss of PCSK7/Pcsk7 leads to apoB100 degradation,” the group wrote in the journal Metabolism. They added that this absence also triggered a “cascade of events” that eventually reduced the accumulation of lipids in the liver, leading to an “effective recovery” from NAFLD.

Having established the role and importance of PCSK7, the group then worked with colleagues at the Montreal Clinical Research Institute (IRCM) to develop an RNA-based therapy targeting the protein in the wild type mice.

The antisense oligonucleotide they devised had galactose (GalNAc) moieties to it in order to target liver hepatocytes and induce the degradation of PCSK7 mRNA.

After being injected into the WT mice, the ASO also successfully reversed diet-induced NAFLD, demonstrating that it may prove a viable therapy for targeting the disease in humans.

The Montreal researchers are now testing their ASO to determine if its efficacy is repeated in human cells, and also plan to experiment on humanised PCSK7 mice. If successful, these investigations could then lead to human clinical trials.

“Given the unexpected role of PCSK7 in enhancing the secretion of apoB via its chaperone-like activity, silencing PCSK7 expression in hepatocytes may be beneficial in treating NAFLD,” the researchers concluded.

“Our data reveal hepatic PCSK7 as one of the major regulators of apoB, and its absence reduces apoB secretion from hepatocytes favoring its ubiquitination and degradation by the proteasome.

“This results in a cascade of events, eventually reducing hepatic lipid accumulation, thus supporting the notion of silencing PCSK7 mRNA in hepatocytes for targeting NAFLD.

“In the future, it may be feasible to develop a biodegradable lipid nanoparticle-based delivery system to carry a single-guide RNA for in vivo editing via hepatocyte-targeted CRISPR-base editing of PCSK7, as was elegantly done for PCSK9.”