Inhibition of influenza virus production in virus-infected mice by RNA interference

Abstract

Influenza A virus infection is a major source of morbidity and mortality worldwide. Because the effectiveness of existing vaccines and antiviral drugs is limited, development of new treatment modalities is needed. Here, we show that short interfering RNAs (siRNAs) specific for conserved regions of influenza virus genes can prevent and treat influenza virus infection in mice. Virus production in lungs of infected mice is reduced by siRNAs given either before or after initiating virus infection, by using slow i.v. administration of small volumes containing siRNAs in complexes with a polycation carrier. Similar effects also are observed when mice are given DNA vectors i.v. or intranasally, from which siRNA precursors can be transcribed. Development of delivery systems that may be compatible with human use demonstrates the potential utility of siRNAs for prophylaxis and therapy of influenza virus infections in humans.

Reconstituted influenza virus envelopes as an efficient carrier system for cellular delivery of small-interfering RNAs

“…Possible target diseases include respiratory infections like influenza infection itself and the severe acute respiratory syndrome for which siRNA-based therapeutic approaches are already under development. 21,[65][66][67][68][69][70][71] In summary, virosomes combine the advantages of synthetic delivery systems (well defined, safe) with the desired properties of viral delivery systems (targeting to cells, active translocation of siRNA into the cytoplasm). They may therefore be an attractive addition to the methods for in vivo administration of siRNA, especially where delivery of siRNA to the respiratory epithelium or to cells with Fc receptors like dendritic cells, macrophages, and NK cells is envisaged.…”

“…19,20 Attempts to improve delivery of siRNA in vivo include complexation of siRNA to polyethylenimine, formulation of siRNA with cationic lipids or collagen derivatives, and entrapment of siRNA in biodegradable microspheres. 19,[21][22][23][24][25] Most of these approaches aim primarily at improving the protection of siRNA from degradation and prolonging the circulation time. While this is indeed a crucial issue, efficient translocation of siRNA into the cytosol of the target cells is also of utmost importance.…”

Liposome Formulations of Hydrophobic Drugs

“…4b). (27,28). Furthermore, it appears likely that liposome based delivery systems modified by specific targeting functions to antigen presenting cells are well suited to further amplify the immune responses that mediate protection against viral infections or rapidly growing tumors.…”

Microenvironmental regulation of biomacromolecular therapies

“…The success of nucleo tide therapies depends on the efficiency of their passage through the cell membrane and subsequent activation or deactivation of target gene expression. Extensive efforts have been made to enhance the efficiency of pDNA 104 and siRNA therapies 105 as non-viral delivery vectors are increasingly being used because of the safety concerns related to the immunogenicity of viral vectors. These efforts comprise complexation with an array of synthetic delivery molecules, including positively charged lipids, polymers, dendrimers and nano-sized particles and wires; encapsulation of pDNA into artificial virus particles 19,21 ; and use of several physical stimulatory tools 106,107 .…”

“…However, the development of these therapies is following a similar path to pDNA approaches (for example, complexation with polycations to enhance the passage of pDNA across the cell membrane 105 ), and it is likely that aspects of the cellular microenvironment that regulate the cellular response to pDNA, will also modulate the cellular response to oligonucleotides and siRNA. These in vitro studies have motivated several strategies aimed at improving in vivo therapeutic efficiency of nucleotides, as described in the next section.…”