ORIGINALLY PUBLISHED
22 April 2022
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 more than five years to identify and validate novel therapeutic targets for NASH, a chronic liver disease which can have serious, life-threatening consequences.
There are currently no approved treatments for NASH and we believe that there is great potential to change this by targeting genetic factors such as PNPLA3 that we reported in Molecular Metabolism in 2019, and HSD17β13, as well as PSD3 a variant that we reported in Nature Metabolism in 2022.1 We have examined these opportunities and others in a review in the Journal of Hepatology, which is part of their collection on therapeutic approaches in NASH.2
Understanding NASH
Cases of non-alcoholic fatty liver disease (NAFLD) and its more serious variant NASH are on the rise, but therapeutic options remain limited.3,4 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.5
NASH is a complex disease with multiple drivers, including strong genetic factors.3 Our early research has focused on identifying genetic targets in order to develop tailored therapies for this disease.
Many of the genetic variants linked to NASH affect lipid metabolism in the liver. Some variants, such as PNPLA3, contribute to NASH risk while others, such as HSD17β13, are protective. Both types can inform the development of precision medicine treatments that either suppress or replicate their effects.
The ability to specifically target genetic variants in NASH is being enabled by new drug modalities. For example, nucleotide therapies such as antisense oligonucleotides provide a way to reduce the expression of disease-associated genes and can be targeted for delivery to the liver.
In combination with affordable companion diagnostic tests, these new approaches could provide highly effective new treatments that are selected for patients based on their genetic characteristics. We envision a future for NASH therapies based on a range of drugs targeting different disease drivers that are guided by diagnostic tests and a precision medicine framework to offer the right treatment to the right patients at the right time.
Watch our video to find out more about our work on PSD3
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.
