Therapeutic opportunities for the treatment of NASH with genetically validated targets

Daniel Lindén; Stefano Romeo

doi:10.1016/j.jhep.2023.05.007

Therapeutic opportunities for the treatment of NASH with genetically validated targets

J Hepatol. 2023 Oct;79(4):1056-1064. doi: 10.1016/j.jhep.2023.05.007. Epub 2023 May 17.

Authors

Daniel Lindén¹, Stefano Romeo²

Affiliations

¹ Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden. Electronic address: daniel.linden@astrazeneca.com.
² Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy. Electronic address: stefano.romeo@wlab.gu.se.

PMID: 37207913
DOI: 10.1016/j.jhep.2023.05.007

Abstract

The identification of genetic variants associated with fatty liver disease (FLD) from genome-wide association studies started in 2008 when single nucleotide polymorphisms in PNPLA3, the gene encoding patatin-like phospholipase domain-containing 3, were found to be associated with altered hepatic fat content. Since then, several genetic variants associated with protection from, or an increased risk of, FLD have been identified. The identification of these variants has provided insight into the metabolic pathways that cause FLD and enabled the identification of potential therapeutic targets. In this mini-review, we will examine the therapeutic opportunities derived from genetically validated targets in FLD, including oligonucleotide-based therapies targeting PNPLA3 and HSD17B13 that are currently being evaluated in clinical trials for the treatment of NASH (non-alcoholic steatohepatitis).

Keywords: CIDEB; Drug development; FLD; GPAM; GPAT1; HSD17B13; MAFLD; MARC1; MASLD; MBOAT7; MTARC1; NAFLD; NASH; PNPLA3; PSD3; SLD guidelines; adiponutrin; precision medicine; steatotic liver disease.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Liver / metabolism
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / genetics
Non-alcoholic Fatty Liver Disease* / metabolism
Polymorphism, Single Nucleotide