Written by:
Bader Zarrouki
Senior Director, BioScience Metabolism, CVRM, BioPharmaceuticals R&D, AstraZeneca
Mathias Liljeblad
Associate Principal Scientist, Translation Science and Experimental Medicines, CVRM, BioPharmaceuticals R&D, AstraZeneca
Nonalcoholic steatohepatitis (NASH) is a leading cause of liver disease around the world and numbers are expected to rise. NASH has a significant unmet medical need with no approved drugs. The emerging understanding of NASH biology and potential new genetically-validated drug targets hold the promise of providing patients with effective treatments.
NASH is a chronic, progressive liver disease in which fat accumulates in liver cells (steatosis), causing inflammation and injury. This can result in scar tissue (fibrosis) and liver damage which may ultimately require a transplant.1 Progressive NASH can also lead to a liver cancer called hepatocellular carcinoma (HCC), and even death.1 Diagnostic difficulties and a lack of understanding of the mechanisms of NASH have meant that treatment options are limited.
Fortunately, that appears to be changing and precision medicine is anticipated to play a key role.2 Our precision medicine approach – targeting the right patient, with the right medicine aims to improve outcomes for NASH patients.
Omics technologies, such as wide-scale genomics, has enabled identification of new disease-causing gene variants. Indeed, research has shown that in the PNPLA3 gene, a single nucleotide substitution severely impairs normal fat breakdown in liver cells and dramatically increases the risk of developing all NAFLD hallmarks, with up to a 10 fold higher risk of developing HCC.3 An other example is for the the HSD17B13 gene, where a single nucleotide substitution leading to loss-of-function (LoF) of this enzyme, confers a protective effect against NASH, fibrosis, cirrhosis, HCC and liver-related mortality.4,5
Learn more about how we want to target the PNPLA3 gene as a potential precision medicine in the below video:
In further research published in April 2022 in Nature Metabolism, researchers described a gene variant in PSD3 which has a protective effect against NASH and fatty liver disease (FLD).6 Our scientists and collaborators also showed that downregulation of PSD3 reduced intracellular lipid level in liver cells and that ASO therapy protected against NASH and liver fibrosis in a preclinical model, supporting PSD3 as a genetically validated target for future NASH therapy.6
Targeting novel biology using nucleotide therapeutics
As we uncover novel disease targets, our chemists and biochemists are leveraging new technologies to create the next generation of therapeutics – going beyond traditional small molecules, monoclonal antibodies and peptides. Nucleotide-based therapeutics offer the advantage of being able to selectively disrupt protein expression induced by these variants using novel liver-targeted antisense oligonucleotides (ASOs).
Through a collaboration with Ionis Pharmaceuticals, we are investigating how ASOs may downregulate the harmful PNPLA3 variant with the aim of restoring fat break down in the liver, or to mimic the protective effects of the LoF mutation in the HSD17B13 gene.
Having reported the first preclinical evidence that PNPLA3 ASO therapy improved multiple stages of NASH, including lipid accumulation, inflammation and fibrosis, and suppressed expression of the PNPLA3 148M protein,7 the next step is to investigate the same approach in clinical studies. In a second programme, we are exploring the potential of ASO therapy to treat patients without the HSD17B13 protective variant which, in human genetic studies, have been shown to rather protect against more advanced forms of liver disease, including HCC and liver-related mortality, but not steatosis.4,9 Thus, by mimicking the protective HSD17B13 LoF mechanism, it may be possible to prevent disease progression or even reduce liver damage.
To optimise this precision medicine approach, it is essential that we deliver ASOs in the relevant liver cells where they are needed. Our ASOs are therefore attached to N-acetylgalactosamine (GalNAc), a sugar molecule that is recognised by receptors on hepatocytes and rapidly taken up inside the cells along with its ASO cargo. This selective uptake is designed to deliver treatment at the right dose and in the right place in order to minimise side effects.
The search for non-invasive NASH diagnostics
Liver biopsy is currently used to confirm NASH diagnosis but is invasive, carries a risk of bleeding, is expensive and is not well suited to ongoing monitoring of disease progression. We are therefore supporting research to identify non-invasive diagnostic biomarkers for use in our clinical trials and, subsequently, in clinical practice. We are active in both the academia-industry research consortia Litmus in Europe and NIMBLE in the USA, which aim to develop and robustly validate potential blood and imaging biomarkers for NASH.
Our scientists are also collaborating with leading academic and commercial partners at the University of Newcastle, UK, Nashville Biosciences, USA, and the University of Hong Kong, to conduct whole genome sequencing in cohorts of patients with NASH. They are investigating the genetic drivers of fibrosis and disease progression to better understand the biology of the disease, and identify potential new targets and biomarkers for precision medicine. Through these collaborations and our clinical trial programmes we will analyse DNA and clinical data from diverse populations to gain new insights that we hope will take us closer to accurate, patient-friendly diagnostics.
In less than 10 years, we hope to demonstrate that the precision medicine approach can provide significant benefit for patients with NASH. We need to show that improvements in histological assessments of NASH in these patients translate into beneficial effects on hard outcomes such as HCC and mortality. We also need a better understanding of the mechanisms of action of the variants in PNPLA3, HSD17B13 and PSD3 and other genes implicated in NASH, and how they interact and may be targeted by combination treatment. It’s an exciting time for NASH research and we are very encouraged by what we have already achieved.
