Genomic data may be key to improving NASH treatment and outcomes

Nonalcoholic steatohepatitis (NASH) is a serious form of nonalcoholic fatty liver disease (NAFLD) characterized by progressive fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Currently, the global prevalence of NASH in adults is 25–30% and is expected to increase to 55.7% by 2040. A 2022 systematic review found that NASH is predicted to become the leading cause of liver transplantation in the US by 2025 and is associated with a significant and increasing economic burden, healthcare resource utilization (HCRU), direct and indirect costs. The national economic burden of NAFLD in terms of direct annual medical costs has been estimated at $103 billion in the US, €27.7 billion in three European countries combined (Germany, France, Italy) and £5.24 billion in the UK.

Unfortunately, diagnosing NASH often requires expensive and invasive tests, and there are currently no approved pharmacological treatments. To close this diagnostic and treatment gap, scientists are looking to data from whole genome, whole exome, and RNA sequencing to provide a more complete biological understanding of NASH, and to reveal novel biomarkers that can be used in non-invasive diagnostics or serve as potential drug targets.

Clinical diagnosis and treatment of NASH

Diagnosis of NASH requires a combination of expensive and invasive tests. The Fatty Liver Program at Cedars-Sinai uses blood tests with subsequent imaging to assess for NASH. Blood tests include liver function tests (ALT and AST), fibrosis assessment for liver scarring (APRI, Fib-4), a lipid profile (blood fats like cholesterol and triglycerides), and possibly hepatitis A & C tests. Imaging tests used include ultrasounds, MRI scans, CT scans, transient elastography, and magnetic resonance elastography. Ultimately though, liver biopsy remains the gold standard for diagnosing NASH.

To date, there is no standard treatment for the condition other than lifestyle changes aimed to mitigate progression. These changes include losing weight, eating a healthy diet, and managing any underlying conditions that may be exacerbating symptoms.

Consequently, there is a strong demand for NASH therapies. Studies are underway to learn more about the underlying mechanisms driving NAFLD and NASH, largely using genome-wide and exome-wide association studies (GWAS, EWAS) and gene expression (mRNA) studies. Pharmaceutical companies look to the data gathered in these studies to find new drug targets for development.

Although there are no current FDA-approved treatments for NASH, several treatments are in late-stage development that target distinct disease mechanisms:

  • Pfizer’s combination therapy, ervogastat/clesacostat, received fast-track designation in May 2022. The combination inhibits the enzymes DGAT2 and ACC that regulate lipid metabolism.
  • Intercept Pharma’s Ocaliva® (obeticholic acid) causes a reduction in MCP-1 mRNA and results in decreased inflammation and fibrosis.
  • Madrigal’s Resmetirom is a thyroid hormone receptor ß-selective (THR-ß) agonist. THR-ß was identified in gene expression studies that showed that decreased THR-ß mRNA expression was associated with liver damage.
  • Inventiva’s candidate, lanifibranor, targets 3 PPAR isoforms, ligand-activated transcription factors that regulate expression of genes responsible for cellular differentiation, development, and tumorigenesis.
  • Galmed’s candidate drug, aramchol, is an SCD1 modulator of hepatic lipid metabolism with anti-fibrotic activity.

Others have pulled out of the market after trial failures including Allergan, NGM Bio, CymaBay, Conatus, Shire, and Gilead. Significant work is underway to develop an effective NASH treatment, yet the lack of approved, effective drugs and non-invasive diagnostics remain a major area of unmet need for patients with a potential market value of $35 billion.

Genomic data can be used to characterize disease, identify biomarkers, and develop new drug targets for NASH

Recent studies have demonstrated that NAFLD is heritable (20-70%), so studies have been performed to identify causal genes that may also serve as therapeutic targets. Early NAFLD studies were limited to the survey of specific gene sets and the study of small sample sets with insufficient clinical data.

Advanced NGS techniques and high-throughput genotyping arrays have enabled unbiased population-scale mapping studies (GWAS, EWAS) that have successfully replicated earlier studies and have identified several genes strongly associated with NAFLD and NASH.

Novel loci linked to specific features of NAFLD using GWAS and EWAS studies

An intensive study of the PNPLA3 variant rs738409, encoding p.I148M, revealed its possible role as a modulator for NASH. A GWAS scan that included over 9,200 individuals from Hispanic, African American, and European American backgrounds discovered genetic variants correlating to discrepancies in hepatic fat content. The findings indicated that variation within PNPLA3 was associated with ancestry-related and inter-individual differences in hepatic fat content, which then led to higher susceptibility towards NAFLD. Follow-up GWAS and EWAS have further defined the relationship between PNPLA3 and steatosis and indicate that this variant is the most strongly associated variant with the full spectrum of NAFLD expression and could increase the risk of NASH.

A missense variant, rs58542926 of TM6SF2, encoding p.E167K was identified in a GWAS initially as being associated with hepatic fat content. Since this discovery, further study has revealed its association with the full spectrum of NAFLD phenotypes, NASH, and cirrhosis. Whole exome sequencing of 46,544 samples uncovered a loss-of-function, protein truncating variant in gene HSD17B13 (rs72613567:TA) that is associated with protection against fibrosis and lower rates of NASH. The variant is not associated with NAFLD, suggesting that the HSD17B13 gene may be involved in advanced stages of NAFLD. This discovery led to the development of ARO-HSD, an RNAi therapeutic that targets HSD17B13 mRNA in liver cells, and has been shown to improve NASH outcomes.

Additional loci have been identified in research studies but have not yet been verified to be associated with NAFLD/NASH due to limitations in study size. Some of these markers of interest include MARC1, PYGO1, LYPLAL1. Larger sample sizes or data sets are needed to conduct confirmatory studies and evaluate these markers as potential drug targets.

Gene expression studies used in therapy development

Gene expression analysis in NASH liver biopsies using qPCR gene expression panels indicated a decrease in thyroid hormone receptor-ß (THR-ß) mRNA expression and activity in liver cells, and that THR-ß expression further decreases with higher stages of NAFLD. THR-ß activity is important for regulation of mitochondrial activities driving the breakdown of liver fat. This crucial discovery has led to the development of Madrigal’s Resmetirom, a treatment that is centered on restoring THR-ß signaling in the liver and is in late-stage development.

Additional genomic data can strengthen the significance of findings

Multiple genome-wide and exome-wide association studies and gene expression studies have been conducted to find genetic associations with the various stages and features (steatosis, fibrosis, inflammation) of NAFLD and NASH. Some genes, like HSD17B13 and THR-ß, have been identified and subsequently used as therapeutic targets. Yet much remains to be understood about these disease states and the genetic factors driving progression.

Advances in sequencing technology are enabling research using larger, richer multi-omic data sets that are associated with various stages of clinical disease. Analysis of large sample sets can help to reduce bias incurred in studies using small cohorts or limited biopsy samples and will help to achieve a statistical power needed to confirm the discovery of significant biomarkers in NAFLD and NASH. Ultimately, novel biomarkers can be used to develop non-invasive diagnostics and potentially serve as novel therapeutic targets.

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