Inhibition of replication of hepatitis B virus in transgenic mice following administration of hepatotropic lipoplexes containing guanidinopropyl-modified siRNAs

Chronic infection with hepatitis B virus (HBV) occurs commonly and complications that arise from persistence of the virus are associated with high mortality. Available licensed drugs have modest curative efficacy and advancing new therapeutic strategies to eliminate the virus is therefore a priority...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of controlled release 2015-07, Vol.209, p.198-206
Hauptverfasser: Marimani, Musa D., Ely, Abdullah, Buff, Maximilian C.R., Bernhardt, Stefan, Engels, Joachim W., Scherman, Daniel, Escriou, Virginie, Arbuthnot, Patrick
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Chronic infection with hepatitis B virus (HBV) occurs commonly and complications that arise from persistence of the virus are associated with high mortality. Available licensed drugs have modest curative efficacy and advancing new therapeutic strategies to eliminate the virus is therefore a priority. HBV is susceptible to inactivation by exogenous gene silencers that harness RNA interference (RNAi) and the approach has therapeutic potential. To advance RNAi-based treatment for HBV infection, use in vivo of hepatotropic lipoplexes containing siRNAs with guanidinopropyl (GP) modifications is reported here. Lipoplexes contained polyglutamate, which has previously been shown to facilitate formulation and improve efficiency of the non-viral vectors. GP moieties were included in a previously described anti-HBV siRNA that effectively targeted the conserved viral X sequence. Particles had physical properties that were suitable for use in vivo: average diameter was approximately 50–200nm and surface charge (zeta potential) was +65mV. Efficient hepatotropic delivery of labeled siRNA was observed following systemic intravenous injection of the particles into HBV transgenic mice. Good inhibition of markers of viral replication was observed without evidence of toxicity. Efficacy of the GP-modified siRNAs was significantly more durable and formulations made up with chemically modified siRNAs were less immunostimulatory. An RNAi-mediated mechanism was confirmed by demonstrating that HBV mRNA cleavage occurred in vivo at the intended target site. Collectively these data indicate that GP-modified siRNAs formulated in anionic polymer-containing lipoplexes are effective silencers of HBV replication in vivo and have therapeutic potential. [Display omitted]
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2015.04.042