How successful has targeted RNA interference for hepatic fibrosis been?

ABSTRACT

Introduction: Exposure to toxins from the portal circulation, viral infection and by-products of metabolic activity make liver tissue prone to injury. When sustained, associated inflammation leads to activation of hepatic stellate cells (HSCs), deposition of extracellular matrix (ECM) proteins and complicating hepatic fibrosis.

Areas covered: In this article, the authors discuss utility of therapeutic gene silencing to disable key steps of hepatic fibrogenesis. Strategies aimed at inhibiting HSC activation and silencing primary causes of fibrogenesis, such as viruses that cause chronic hepatitis, are reviewed. Both synthetic and expressed artificial intermediates of the RNAi pathway have potential to treat hepatic fibrosis, and each type of gene silencer has advantages for clinical translation. Silencing expression cassettes comprising DNA templates are compatible with efficient hepatotropic viral vectors, which may effect sustained gene silencing. By contrast, synthetic short interfering RNAs are amenable to chemical modification, incorporation into non-viral formulations, more precise dose control and large scale preparation.

Expert opinion: Clinical translation of RNAi-based technology for treatment of hepatic fibrosis is now a realistic goal. However, achieving this aim will require safe, efficient delivery of artificial RNAi intermediates to target cells, economic large scale production of candidate drugs and specificity of action.

KEYWORDS:

• Hepatic fibrosis
• RNAi
• hepatocytes
• hepatic stellate cells
• extracellular matrix

Article highlights

• Although causes of liver injury are varied, common mechanisms of hepatic fibrosis lead to activation of hepatic stellate cells, formation of hepatic myofibroblasts and deposition of extracellular matrix proteins.

• Improved understanding of RNA interference (RNAi) has enabled development of gene silencers that are capable of inactivating key steps of the hepatic fibrogenesis pathway.

• Both expressed and synthetic gene silencers have successfully been employed in an attempt to arrest fibrogenesis in small animal models of the disease process. Clinical translation will depend on efficient delivery of the silencing nucleic acids, specificity of action and good silencing without off-target effects.

• Primary causes of hepatic fibrosis, e.g. hepatitis B virus and hepatitis C virus, have been targeted using RNAi-based gene silencing. In addition several downstream fibrogenic targets, e.g. the gene encoding connective tissue growth factor, have been inactivated with good efficacy.

• Progress with developing RNAi-based therapy for hepatic fibrosis shows promise, and outcomes from current clinical evaluations are keenly awaited.

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Declaration of interest

Pharmaceutical industry support has come from Johnson & Johnson Innovation. The South African Medical Research Council, South African National Research Foundation and Poliomyelitis Research Foundation are statutory bodies that have also provided support for this research. The authors have no other 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 apart from those disclosed.

Additional information

Funding

Pharmaceutical industry support has come from Johnson & Johnson Innovation. The South African Medical Research Council, South African National Research Foundation and Poliomyelitis Research Foundation are statutory bodies that have also provided support for this research.