siRNA drug development against hepatitis B virus infection

ABSTRACT

Introduction: Hepatitis B virus (HBV) infection is the worldwide leading cause of liver cirrhosis and hepatocellular carcinoma. Currently available medication can suppress viral replication in the majority of patients, but clearance of the viral antigens can be achieved in only about 10%.

Areas covered: RNA interference is a very attractive therapeutic option since a well-designed compound could possibly inhibit all HBV mRNA and thus synthesis of all its antigens, which could combine antiviral and immunomodulatory modes of action. The aim of the article is to provide current knowledge on possible use of small interfering RNA (siRNA) molecules in the treatment of chronic HBV infection.

Expert opinion: Based on the current status of clinical trials, we should expect that within the coming five years at least one siRNA molecule will be registered for clinical use. However, most important at this stage of development will be the safety profile, improving the route of administration, selection of the optimal combination with other anti-HBV drugs (nucleoside analogues, interferons) and finally selection of the optimal system introducing siRNA molecules into infected cells. Current therapeutic options for HBV, the siRNA mechanism of action, as well as preclinical and clinical studies with siRNA molecules are presented in this article.

KEYWORDS:

• HBs antigen
• HBV
• immunomodulation
• liver cirrhosis
• viral hepatitis
• viral suppression

Article Highlights

• Currently available therapeutic options for chronic hepatitis B are not efficient enough to cure a large majority of patients.

• Among several currently studied compounds small interfering RNA (siRNA) molecules seem to be the most promising future therapeutic option for HBV infection, due to their possible effect on synthesis of viral antigens and indirect immunomodulatory effects.

• Preclinical studies carried out with several siRNA molecules shown inhibition of HBsAg, HBeAg and HBV DNA synthesis and additionally reduction of cccDNA content.

• Promising efficacy and good safety profile were confirmed in early stage clinical studies. The most advanced in development are ARC-520 and ARB-1467, but recently reported results from the study with novel AB-729 molecule demonstrated the highest potency.

• Since efficacy of siRNA based therapy seems to be superior to currently available treatment options, we should expect that within the coming five years at least one siRNA molecule will be registered for clinical use.

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

Additional information

Funding

This paper was not funded.