title: Inhibition of hepatitis B virus replication in vivo using lipoplexes containing altritol-modified antiviral siRNAs.
abstract: Chronic infection with the hepatitis B virus (HBV) occurs in approximately 6% of the world's population and carriers of the virus are at risk for complicating hepatocellular carcinoma. Current treatment options have limited efficacy and chronic HBV infection is likely to remain a significant global medical problem for many years to come. Silencing HBV gene expression by harnessing RNA interference (RNAi) presents an attractive option for development of novel and effective anti HBV agents. However, despite significant and rapid progress, further refinement of existing technologies is necessary before clinical application of RNAi-based HBV therapies is realized. Limiting off target effects, improvement of delivery efficiency, dose regulation and preventing reactivation of viral replication are some of the hurdles that need to be overcome. To address this, we assessed the usefulness of the recently described class of altritol-containing synthetic siRNAs (ANA siRNAs), which were administered as lipoplexes and tested in vivo in a stringent HBV transgenic mouse model. Our observations show that ANA siRNAs are capable of silencing of HBV replication in vivo. Importantly, non specific immunostimulation was observed with unmodified siRNAs and this undesirable effect was significantly attenuated by ANA modification. Inhibition of HBV replication of approximately 50% was achieved without evidence for induction of toxicity. These results augur well for future application of ANA siRNA therapeutic lipoplexes.
authors.affiliation: Antiviral Gene Therapy Research Unit; School of Pathology; University of the Witwatersrand Medical School; South Africa.
authors.forename: Justin
authors.initials: J
authors.lastname: Hean
authors.forename: Carol
authors.initials: C
authors.lastname: Crowther
authors.forename: Abdullah
authors.initials: A
authors.lastname: Ely
authors.forename: Rafique
authors.initials: R
authors.lastname: Ul Islam
authors.forename: Samantha
authors.initials: S
authors.lastname: Barichievy
authors.forename: Kristie
authors.initials: K
authors.lastname: Bloom
authors.forename: Marc S
authors.initials: MS
authors.lastname: Weinberg
authors.forename: Willem Al
authors.initials: WA
authors.lastname: van Otterlo
authors.forename: Charles B
authors.initials: CB
authors.lastname: de Koning
authors.forename: Felix
authors.initials: F
authors.lastname: Salazar
authors.forename: Patricia
authors.initials: P
authors.lastname: Marion
authors.forename: Eric B
authors.initials: EB
authors.lastname: Roesch
authors.forename: Marc
authors.initials: M
authors.lastname: Lemaitre
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
authors.forename: Patrick
authors.initials: P
authors.lastname: Arbuthnot