RNA Interference: A Promising Approach for the Treatment of Hepatitis B Virus (HBV) InfectionAugust 18, 2017
By Cornelius Omatola
HBV infection is global health problem with over 350 million HBV carriers worldwide and over one million deaths occurring annually due to HBV-induced liver diseases. Current therapy which includes IFN-? and nucleoside analogs such as lamivudine are partially effective. Disadvantages of these drugs include low efficacy, severe side effects, and occurrence of resistance due to HBV mutations. There is need for an ideal treatment that would be very short duration, have high cure rates, fewer side effects and broad coverage.
RNA interference (RNAi) is a process by which small interfering RNA (siRNA) with specific sequences induce silencing of homologous genes by binding to their complementary mRNA and inducing the elimination of the mRNA. RNAi has shown antiviral effect against HBV, HCV, HPV, and HIV in many studies and unlike HCV and HIV, the small size genome and presence overlapping reading frames (ORFs) in HBV makes it more susceptible to RNAi.
In terms of attributes, RNAI-based therapy holds a lot of advantages over current therapies. For example, siRNA mediated inhibition of gene expression does not require any viral DNA replication, and siRNA combinations have the ability to target conserved regions of the viral genome. Also, there is an obvious reduction of HBV DNA from infected hepatocyte. Furthermore, because RNAi-based drugs can be expressed from introduced genes, they offer the possibility for a sustained therapeutic response. They are also specific and potent in their actions.
Though RNAi-based therapies are obviously effective, there are many factors and challenges militating against their application. One of these is the delivery mechanisms to the cells/organs and the issue of bioavailability and stability of siRNAs. However, the issue of delivery methods have been resolved through the uses of cationic liposome which contains lipid with positively charged group (e.g cholesteryl spermine) that form complexes with siRNA and cationic polymer which like liposome, also form complexes with the negatively charged phosphate groups of the siRNA e.g. NAG-MLP. Also, in vivo stability of siRNA has been improved via chemical modification of backbone with 2?F, 2?O-Methyl, and 2’H to substitute 2’-OH residues required for nuclease activity
One of the drugs which have been developed to treat HBV infection through the use of RNAi is ARC-520, a drug designed to target the X protein of the virus. This has been found out to lead to reduction in viral replication, viral protein synthesis, and ultimately to reduction in viral antigen and immune suppression.
In laboratory animal’s experiments, a single low dose of ARC-520 was found to result in above 95% reduction of HBV RNA, proteins (e.g. HBeAg and HBsAg), and viral DNA, with long duration of effect in mouse and chimpanzee models of HBV infection. In chimpanzee, levels of HBV DNA, eAg, sAg only return to baseline after 43, 43, and 71 days respectively of dosing.
As at 2013, ARC-520 has gone through phase-1-clinical trials. Results of a phase 1 from first-in-human safety and tolerability studies conducted among 36 patients with chronic HBV showed that the drug was reasonably safe and well tolerated. No dropout was recorded for any reason and no serious adverse effect was experienced.
In conclusion, the use of RNAi pathway as a new approach in antiviral drug discovery is promising as the genetic distance between mammalian and HBV genome represents an advantage in minimizing off-target hits and reducing possible side effects. Also, the ability of RNAI to effectively and durably halt viral protein production can lead to complete HBsAg loss and conversion to seronegative status which eliminates long treatments and patient compliance issues. However, improvements in safety and efficacy of delivery methods remain an important objective.
(RNA Interference: A Promising Approach for the Treatment of Hepatitis B virus Infection is an abstract of a seminar presented at the Department of Virology, University of Ibadan.)