Synthetic mRNA Gene Therapies and Hepatotropic Non-viral Vectors for the Treatment of Chronic HBV Infections

Abstract

Hepatitis B virus (HBV) infection remains a global health challenge with an estimated 296 million people chronically infected, leading to a high incidence of HBV-associated liver cancer and cirrhosis. Currently, there is no cure for chronic HBV infection, and novel therapeutic approaches, including gene editing and epigenome engineering, are being investigated. Although promising, the liver-specific delivery, expression and safety profile of these gene therapies requires careful consideration as off-target effects could result in genotoxicity. Recent advances in the field of synthetic mRNA therapeutics may help to overcome some of the hurdles currently associated with delivery and expression of these gene therapies for HBV. In vitro transcription (IVT) and capping can now be achieved using good manufacturing practice (GMP) grade materials. The inclusion of modified bases and sequence optimization, particularly at the 5′ and 3′ untranslated regions (UTRs), improves in situ translation by enhancing RNA stability. Non-viral vector formulations, for instance, ligand-modified nanoparticles, could be used to direct anti-HBV mRNA therapies directly to hepatocytes. Finally, the transient expression of synthetic mRNAs allows for better dose regulation and improved safety, particularly when using gene editing tools. This chapter will discuss the recent advances that could be used to expand and improve on synthetic mRNA gene therapies for chronic HBV infection.