The liver is a key production and processing site that is essential for health. Liver dysfunction can result in both systemic and liver-specific diseases. To combat these diseases, genetic approaches have been developed that have high liver tropism and are based on gene addition/editing or gene silencing. The gene addition/editing approach has yielded encouraging clinical data on the use of viral vectors in patients with haemophilia, as well as neuromuscular diseases, and has led to trials for liver-related disorders. However, the immune response and the long-term stability of exogenous expression remain important challenges. Gene editing and mRNA therapy have yielded first in-human proof-of-concept therapeutics and vaccines, but the road to the treatment of liver-related disorders remains long. Gene silencing is accomplished primarily via antisense oligonucleotides and small-interfering RNAs (siRNAs). siRNA modification with N-acetyl galactosamine results in hepatocellular-specific targeting and catapulted the liver to the centre of siRNA research. Several siRNA drugs for liver-related disorders have recently been approved, and the pipeline of drugs under investigation is crowded. Loss-of-function mutations might also be treated with enzyme substitution therapy. This review summarises current genetic approaches as well as key enzyme substitution therapies, focusing on recently approved compounds, potential adverse effects, and future challenges. Collectively, these recent advances place the liver at the forefront of precision medicine for metabolic and genetic diseases and are expected to transform the care and treatment of patients with both liver-specific and systemic diseases.
Keywords: gene addition; gene editing; gene silencing; gene therapy; liver disease; monogenic defects.
Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.