Author: Amy C. H. Lee ; Ian MacLachlan ; Thomas W. Geisbert ; Erik Zhaoying Yu ; Lisa E. Hensley ; Peter B. Jahrling ; Elizabeth A. Fritz ; Kevin McClintock ; Janet R. Phelps ; Adam Judge ; Joan B. Geisbert ; Lloyd B. Jeffs ; Elliott Kagan ; Kathleen Daddario-DiCaprio

BACKGROUNDEbola virus (EBOV) infection causes a frequently fatal hemorrhagic fever (HF) that is refractory to treatment with currently available antiviral therapeutics. RNA interference represents a powerful, naturally occurring biological strategy for the inhibition of gene expression and has demonstrated utility in the inhibition of viral replication. Here, we describe the development of a potential therapy for EBOV infection that is based on small interfering RNAs (siRNAs).METHODSFour siRNAs targeting the polymerase (L) gene of the Zaire species of EBOV (ZEBOV) were either complexed with polyethylenimine (PEI) or formulated in stable nucleic acid-lipid particles (SNALPs). Guinea pigs were treated with these siRNAs either before or after lethal ZEBOV challenge.RESULTSTreatment of guinea pigs with a pool of the L gene-specific siRNAs delivered by PEI polyplexes reduced plasma viremia levels and partially protected the animals from death when administered shortly before the ZEBOV challenge. Evaluation of the same pool of siRNAs delivered using SNALPs proved that this system was more efficacious, as it completely protected guinea pigs against viremia and death when administered shortly after the ZEBOV challenge. Additional experiments showed that 1 of the 4 siRNAs alone could completely protect guinea pigs from a lethal ZEBOV challenge.CONCLUSIONSFurther development of this technology has the potential to yield effective treatments for EBOV HF as well as for diseases caused by other agents that are considered to be biological threats.

01 May 2005·Biochimica et Biophysica Acta (BBA) - Biomembranes

Stabilized plasmid–lipid particles containing PEG-diacylglycerols exhibit extended circulation lifetimes and tumor selective gene expression

Article

Author: Palmer, L. ; Ambegia, E. ; Ansell, S. ; Cullis, P. ; Heyes, J. ; MacLachlan, I.

Stabilized plasmid lipid particles (SPLP) consist of a single copy of DNA surrounded by a lipid bilayer. The particles are small ( approximately 100 nm), stable, monodisperse and have a low surface charge. A diffusible polyethylene glycol (PEG) coating attached to a lipid anchor is critical to the SPLP's functionality. The PEG-lipid exchanges out of the bilayer at a rate determined by the size of the lipid anchor. Here we show that SPLP can be prepared using a series of PEG-diacylglycerol lipids (PEG-S-DAGs). SPLP were prepared incorporating PEG-dimyristoylglycerol (C14), PEG-dipalmitoylglycerol (C16) or PEG-distearoylglycerol (C18) and the rate of PEG-lipid diffusion from the bi-layer determined using a FRET assay. SPLP pharmacokinetics confirm a correlation between the stability of the PEG-lipid component and circulation lifetime. PEG-S-DAGs with longer lipid anchors yield more stable SPLP particles with longer circulation half-lives yielding an increase in tumor delivery and gene expression. PEG-distearoylglycerol (C18) containing SPLP bypass so-called 'first pass' organs, including the lung, and elicit levels of gene expression in distal tumor tissue 100- to 1000-fold greater than that observed in any other tissue. The incorporation of PEG-S-DAG in SPLP confirms that small size, low surface charge and extended circulation lifetimes are prerequisite to the accumulation and tumor selective expression of plasmid DNA following systemic administration.

01 Jan 2005·Non-Viral Vectors for Gene Therapy, Second Edition: Part 1

“Diffusible‐PEG‐Lipid Stabilized Plasmid Lipid Particles”

Article

Author: Ian MacLachlan ; Pieter Cullis

Many viral and non-viral gene transfer systems suffer from common pharmacological issues that limit their utility in a systemic context. By application of the liposomal drug delivery paradigm, many of the limitations of the first generation non-viral delivery systems can be overcome. Encapsulation in small, long-circulating particles called stabilized plasmid lipid particles (SPLP) results in enhanced accumulation at disease sites and selective protein expression. This work compares the detergent dialysis method of SPLP manufacture with an alternative method, spontaneous vesicle formation by ethanol dilution. The pharmacology of SPLP, as determined by monitoring lipid label and quantitative real time PCR, is also presented.

News (Medical) associated with Protiva Biotherapeutics, Inc.

22 Dec 2006

·www.biospace.com

Protiva Biotherapeutics Files Appeal In INEX Pharmaceuticals Litigation

VANCOUVER, BRITISH COLUMBIA -- (MARKET WIRE) -- December 21, 2006 -- Protiva Biotherapeutics Inc. today filed an appeal with the BC Court of Appeals that seeks to overturn the BC Supreme Court's November 23, 2006 ruling that would permit Inex Pharmaceuticals Corporation to transfer the Inex-Protiva agreements to Tekmira Corporation without Protiva's consent.

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