In Vivo Evidence for Inhibition of Respiratory Viruses

RNAi-mediated virus inhibition has been studied for a large group of RNA viruses (see Table 3). Recent studies in mice suggest that RNAi holds great promise for the prevention and treatment of infection of the respiratory viruses with an RNA genome such as influenza A virus, human parainfluenza virus

(HPIV) and HRSV (Bitko et al. 2005; Ge et al. 2004; Tompkins et al. 2004; Zhang et al. 2005). Due to limitations of anti-influenza vaccines and drugs, there is a real need for novel strategies to inhibit influenza virus. Worldwide, an estimated half million deaths per year are attributed to influenza virus, and there is the continuous threat of the emergence of a novel pandemic strain. To use siRNA as an in vivo therapeutic, it must be delivered efficiently to the appropriate tissue(s), in this case the lungs. Lungs are perhaps the most readily transfectable organs because they are likely the most vascularized tissue in the body. Furthermore, injected materials will first traverse the capillary beds of the lungs upon intravenous administration. Researchers have used polyethyleneimine (PEI) injected intravenously or intratracheally to deliver siRNAs and a lentiviral DNA vector expressing shRNAs (Ge et al. 2004). PEI is a cationic polymer that has been used to deliver DNA into lung cells. Others have delivered anti-influenza siRNAs intranasally with the cationic transfection reagent Oligofectamine (Tompkins et al. 2004). Reduction of the virus titre in the lungs and lethality was observed when the antivirals were administered either prior or subsequent to virus challenge.

Similarly, replication of HRSV and HPIV in mice could be blocked by intranasal delivery of synthetic siRNAs (Bitko et al. 2005). The authors show that this approach is effective both with and without the use of transfection reagents. Besides synthetic siRNAs, also intranasal administration ofplasmids expressing shRNA against HRSV results in a significant decrease of viral titres (Zhang et al. 2005). These findings suggest that low dosages of inhaled or intravenously administered siRNAs/shRNAs might provide an easy and efficient basis for prophylaxis and antiviral therapy against respiratory viruses in human populations.

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