A pharmacological approach to lifestyle related metabolic disorders- does it make anti-sense?

Non-Alcoholic fatty liver disease (NAFLD) is a group of liver diseases that include NAFL and Non-alcoholic steatohepatitis (NASH). It is a chronic progressive disease of the liver not caused by alcohol. It starts with fat accumulation, progresses into inflammation, swelling and liver enlargement (NASH), fibrosis, cell death and replacement of dead cells by scar tissue(cirrhosis) and finally results in cancer (hepatocellular carcinoma). A figure describing this progression has been published by my colleague Maaike Schilperoort in an article describing emerging therapeutic strategies for fatty liver-related cancer. 

NASH is the most severe form of NAFLD before progressing into the irreversible stages of cirrhosis and cancer. It remains under-diagnosed as it is asymptomatic, or it is accompanied by non-specific symptoms. Individuals with hypertension, high cholesterol, who are over-weight or obese, have diabetes or insulin resistance are at a greater risk to develop NASH. It is largely a lifestyle associated metabolic disorder made worse in individuals with obesity and type 2 diabetes. Current treatment modalities focus on lifestyle interventions and management of co-existing conditions. A lack of specific and targeted pharmacological recommendations with proven efficacy complicates NAFLD management.

Junjie Yu and colleagues have conducted a comprehensive study by using data available from a clinical trial of patients with NASH and studying mouse models of NASH. They identified a gene – Jagged 1 (JAG1) that was increased in patients who had NASH and fibrosis. They used this key finding to conduct experiments on mouse models to further study the role of JAG1 in either reducing or worsening NASH and liver fibrosis. They have also used a cell targeted strategy to test potential therapeutic interventions associated with the development of NASH. 

To mimic human NASH, they fed mice with a NASH inducing diet, rich in saturated fat, sucrose, and cholesterol as well as fructose containing drinking water. The mice develop liver steatosis, inflammation, fibrosis, weight gain and insulin resistance which are symptoms seen in patients with NASH. JAG1 was increased in the liver, and this correlated with an increase in fibrotic markers in mice fed a NASH-inducing diet. An interesting observation that directed the rest of the study was that JAG1 was increased in the liver specific cell type called hepatocytes. They used a virus mediated gene delivery method to increase or decrease Jag1 in the hepatocytes of the mice that were fed the NASH-inducing diet. Increasing Jag1 increased fibrosis that is induced by the NASH diet in the mice and decreasing Jag1 protected the mice liver from developing fibrosis. Based on these insights they used a technology called antisense oligonucleotides (ASO) to block Jag1 expression in mice that were fed a NASH-inducing diet. They found mice treated with Jag1-ASO had reduced expression of JAG1 at the gene and protein levels along with a reduction in inflammatory and fibrotic markers. However, as this method would target all cell types, a hepatocyte specific Jag1 inhibitor was developed. Mice fed with NASH-inducing diet on treatment with hepatocyte specific Jag1 inhibition show decreased Jag1 in the liver as well as reduction in liver fibrosis.

This is a very interesting approach that could lead to specific and targeted pharmacological treatment of NASH. ASOs are short single strand nucleotide sequences that can be produced to target specific genes of interest (like Jag1 in this case) in cells. They alter protein expression during the process of translation from RNA to protein (Fig 1). As they are made to target specific genes and cells, they have a higher chance of success. Currently there are 15 FDA approved ASO based drugs for disorders ranging from neurodegenerative disorders to cancer. The main limitation of ASO is the enzymatic degradation of oligonucleotides and removal from the body by the kidneys.  Further research into improving ASO to optimize delivery and safety could lead to development of therapies for disorders that require targeted pharmacological interventions.

Figure 1. A. A schematic of regular transcription and translation processes involved in protein synthesis. B. ASO mediated disruption of protein synthesis. Figure created using Biorender.com

Currently, pharmacological therapies for NAFLDs are recommended for individuals who do not achieve expected weight loss and for those individuals with stage 2 or greater NASH-induced fibrosis. Lifestyle changes may not be possible for all individuals with metabolic disorders due to various reasons including socio-economic reasons, limited food resources, disabilities, etc. Though lifestyle interventions like weight management, maintaining a healthy diet and regular exercise have been shown to reduce symptoms and manage the disorder, it works well if it is diagnosed at earlier stages. However, given that NASH does not have specific symptoms and is grossly under-diagnosed, an option for treatment of the disorder when it is at later stages may alleviate the disease burden. Specific targeted pharmacological approaches towards treating a metabolic disorder would be a feasible approach and may be a more efficient way to treat NAFLD when combined with lifestyle changes.

Reviewed by : Trang Nguyen and Samantha Rossano




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