Gene expression inhibitors for the treatment of liver fibrosis: drugs under preclinical and early clinical investigation

ABSTRACT

Introduction

Liver fibrosis represents an unmet medical condition with growing incidence and only limited therapeutic options. Interfering with dysregulated gene expression was considered a specific treatment approach, and we are here reviewing the current options to modulate transcription and translation with small molecule inhibitors of involved enzymes, transcription factors or by using non-coding RNA molecules (RNA interference) or DNA antisense oligonucleotides. Despite promising results in preclinical models, only limited data are available from studies in humans.

Areas covered

This expert opinion provides a general overview of how to interfere with gene expression (transcription and translation) and highlighting recent achievements in liver fibrosis.

Expert Opinion

Many compounds that were explored to modulate gene expression in liver fibrosis (models) were developed as anti-cancer agents. Their use in humans with impaired liver function is often impaired by the lack of specificity to inhibit only fibrosis-related genes in the liver and by associated general toxicity and narrow therapeutic windows. RNAi approaches show a higher degree of specificity and potentially less systemic toxicity. Clinical development in liver fibrosis requires close interaction between pharmaceutical companies and regulatory authorities to address topics like relevant (surrogate) endpoints to achieve meaningful readouts faster.

KEYWORDS:

• Antisense oligonucleotides
• bromodomain inhibitors
• cyclin-dependent kinase inhibitors
• eIF modulators
• miRNA
• ncRNA
• Pol II inhibitors
• RNAi

Article highlights

• Chronic liver disease leads to fibrosis and cirrhosis via complex inflammatory processes and extracellular accumulation of collagen-related proteins.

• As end-stage liver disease with complete cirrhosis is not yet amenable to drug therapy, inhibition of progression of liver fibrosis is still challenging and has so far been achieved only in experimental settings by various classes of inhibitors of gene transcription and translation.

• BET, CDK and RNA polymerase II inhibitors, as well as nucleoside analogues/inhibitors of transcription, have been shown to reverse fibrosis in animal models by controlling different associated pathways (inflammation, metabolism and stem cells).

• EIF, antisense oligonucleotides, miRNAs and siRNAs are new and promising drugs to slow liver fibrosis by selectively inhibiting translation.

• Based on the experimental inhibition of fibrotic pathogenesis in chronic liver diseases, the first results from clinical trials should lead to the development of transcriptional and translational regulatory drugs with greater efficacy and specificity against the chronic process of liver fibrosis leading to cirrhosis.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.