Liposome-siRNA-Peptide Complexes Cross the Blood-Brain Barrier and Significantly Decrease PrPC on Neuronal Cells and PrPRES in Infected Cell Cultures

Abstract

BackgroundRecent advances toward an effective therapy for prion diseases employ RNA interference to suppress PrPC expression and subsequent prion neuropathology, exploiting the phenomenon that disease severity and progression correlate with host PrPC expression levels. However, delivery of lentivirus encoding PrP shRNA has demonstrated only modest efficacy in vivo.Methodology/Principal FindingsHere we describe a new siRNA delivery system incorporating a small peptide that binds siRNA and acetylcholine receptors (AchRs), acting as a molecular messenger for delivery to neurons, and cationic liposomes that protect siRNA-peptide complexes from serum degradation.Conclusions/SignificanceLiposome-siRNA-peptide complexes (LSPCs) delivered PrP siRNA specifically to AchR-expressing cells, suppressed PrPC expression and eliminated PrPRES formation in vitro. LSPCs injected intravenously into mice resisted serum degradation and delivered PrP siRNA throughout the brain to AchR and PrPC-expressing neurons. These data promote LSPCs as effective vehicles for delivery of PrP and other siRNAs specifically to neurons to treat prion and other neuropathological diseases.

microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain

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Impediment of selenite-induced cataract in rats by combinatorial drug laden liposomal preparation

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Small interfering RNAs: heralding a new era in gene therapy

“…The results confirmed improved efficacy and longer half-life of siRNA encapsulated in SNALPs in the plasma and liver compared to unformulated siRNA (Morrissey 2005). Another newly described delivery vehicle for siRNAs is the liposome-siRNA-peptide complex (LSPCs) that showed a potential in therapy of neurodegenerative disorders (Pulford 2010). For that purpose, intravenous injections were used for transvascular delivery of siRNA complexed with LSPCs across the blood-brain barrier to the brain.…”