Written by:
Daniel Lindén, PhD
Associate Prof, Senior Principal Scientist and Senior Director at Bioscience Metabolism, Research and Early CVRM, BioPharmaceuticals R&D, AstraZeneca
Stefano Romeo, MD, PhD
Prof. Senior Consultant, Principal Investigator, Professor in Molecular and Clinical Medicine at the Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Sweden
Advances in understanding of disease biology and major innovations in gene sequencing and data analysis has created a highly fertile scientific environment to support significant progress in the identification of genetic variants for non-alcoholic steatohepatitis (NASH).
Partnering to push the boundaries of science
We have been collaborating together for around five years to identify and validate novel therapeutic targets for NASH, a chronic liver disease which can have serious, life-threatening consequences.
Our recent high impact publication in Nature Metabolism reports exciting results from this research with the identification of PSD3, a new genetic target that has been shown to be associated with fatty liver disease.1 This is an important discovery which may lead to the development of a future treatment of NASH.
Understanding NASH
Cases of NAFLD and its more serious variant NASH are on the rise, but therapeutic options remain limited.2,3 Fat accumulation in the liver can lead to chronic liver disease with potentially life-threatening complications, including cirrhosis and liver cancer, as well as obesity, type 2 diabetes, and chronic kidney disease.4
NASH is a complex disease with multiple drivers, including strong genetic factors.2 Our early research has focused on identifying genetic targets in order to develop tailored therapies for this disease.
Watch our video to find out more about this exciting discovery
Turning science into medicine
The early R&D process starts with selecting the right target which is arguably one of the most important decisions we need to make.
Step 1: Target identification
In this first step, we focused on 32 gene variants that had previously been found to be associated with circulating triglycerides. We investigated the association of these gene variants with liver fat content in over 2,700 individuals in whom liver fat content was measured by magnetic spectroscopy. This led to the identification of a novel association between the PSD3 variant and reduced liver fat content in this cohort.
Step 2: Target validation
These results were then validated in >1,900 liver biopsy samples from the Liver Biopsy Cohort in European individuals at risk of liver disease. This was confirmed in two additional cohorts, in nearly 11,000 subjects from the UK Biobank and >670 at-risk obese subjects in an independent cohort. We found that downregulation of PSD3 was not only associated with reduced liver fat content but also inflammation and fibrosis which are important factors in patients with fatty liver disease.
Step 3: Lead identification
At Gothenburg University and in collaboration with Ionis Pharmaceuticals we have shown proof-of-concept with extensive in vitro and in vivo testing using small interfering RNA (siRNA) and antisense oligonucleotides (ASOs). We have shown that in primary human hepatocytes cultured in 3D organoids, PSD3 silencing reduced intracellular fat accumulation. Furthermore, treating preclinical models with diet-induced NASH with a liver-targeted PSD3 ASO, reduced liver fat content, inflammation and fibrosis.
Looking to the future
Further studies are needed to fully understand the mechanism of action, but our results could lead to new treatments that target the PSD3 gene to protect patients from excessive liver fat accumulation and progression of FLD, including NASH. We look forward to continuing our collaboration and using the power of genomics to develop targeted treatments for patients.
