Hepatocyte-targeted RNAi Therapeutics for the Treatment of Chronic Hepatitis B Virus Infection

Abstract

RNA interference (RNAi)-based therapeutics have the potential to treat chronic hepatitis B virus (HBV) infection in a fundamentally different manner than current therapies. Using RNAi, it is possible to knock down expression of viral RNAs including the pregenomic RNA from which the replicative intermediates are derived, thus reducing viral load, and the viral proteins that result in disease and impact the immune system's ability to eliminate the virus. We previously described the use of polymer-based Dynamic PolyConjugate (DPC) for the targeted delivery of siRNAs to hepatocytes. Here, we first show in proof-of-concept studies that simple coinjection of a hepatocyte-targeted, N-acetylgalactosamine-conjugated melittin-like peptide (NAG-MLP) with a liver-tropic cholesterol-conjugated siRNA (chol-siRNA) targeting coagulation factor VII (F7) results in efficient F7 knockdown in mice and nonhuman primates without changes in clinical chemistry or induction of cytokines. Using transient and transgenic mouse models of HBV infection, we show that a single coinjection of NAG-MLP with potent chol-siRNAs targeting conserved HBV sequences resulted in multilog repression of viral RNA, proteins, and viral DNA with long duration of effect. These results suggest that coinjection of NAG-MLP and chol-siHBVs holds great promise as a new therapeutic for patients chronically infected with HBV.

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

“…administered, multi-component delivery systems such as lipid nanoparticles (LNPs) and polymers, resulting in a clinical proof of concept for systemic RNAi. 3,4 Although clinical progress has been made with these multi-component systems, they are encumbered by the need for i.v. administration and, in the case of LNPs, pre-medication with steroids to mitigate infusion-related reactions.…”

Lactose-based glycoconjugates with variable spacers for design of liver-targeted liposomes

“…Особенно важно использование технологий направленной доставки лекарств в области генной терапии, зарекомендовавшей себя как достаточно эффективный инструмент медицины последнего десятилетия [2,3]. Генная терапия требует избирательной и локальной стратегии лечения заболеваний, которая может быть обеспечена системами направленной доставки ДНК-или РНК-препаратов [4][5][6].…”

Emerging therapeutics and relevant targets for chronic Hepatitis B

“…Furthermore, this siRNA-induced inhibitory effect was stronger in combination of siRNAs compared with individual use of each siRNA (37). Using a new siRNA delivery system, Wooddell et al (38) presented that siRNAs targeting different sites of HBV induced multilog repression of viral RNA, viral DNA, and protein and the effect lasted for a long duration. ARC-520, designed to reduce the expression and release of viral particles by RNAi mechanism, suppressed the expression of HBV DNA, HBsAg, and hepatitis B e antigen (HBeAg) in a HBV-infected chimpanzee with a high viral titer (39).…”