Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs

Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs

11/23/2004

吳政道

Abstract

Double-stranded short interfering RNAs (siRNAs) mediate post-transcriptional inhibition of gene expression in a variety of biological systems, and the phenomenon RNA interference (RNAi) represents a potential strategy for in vivo target validation and therapeutic product development. However, there are no published reports of systemic activity for siRNAs towards endogenous targets after conventional and clinically acceptable routes of administration. The main obstacle to achieving in vivo gene silencing by RNAi technologies is delivery. In the authors’ previous work(Lorenz et al., 2004), they found that two series of lipophilic siRNAs conjugates can improve the delivery of siRNAs into human liver cells without transfection agents. In this paper(Soutschek et al., 2004), they take advantage of this finding to further determine the in vivo silencing capacity of the chemically modified siRNAs and show that such siRNAs can silence an endogenous gene encoding apolipoprotein B (apoB)(Burnett and Barrett, 2002) after intravenous injection in mice. These findings demonstrate the therapeutic potential of siRNAs for the treatment of disease.

From: Nature. 2004 Nov 11;432(7014):173-8.

References

Burnett,J.R. and Barrett,P.H. (2002). Apolipoprotein B metabolism: tracer kinetics, models, and metabolic studies. Crit Rev. Clin. Lab Sci. 39, 89-137.

Lorenz,C., Hadwiger,P., John,M., Vornlocher,H.P., and Unverzagt,C. (2004). Steroid and lipid conjugates of siRNAs to enhance cellular uptake and gene silencing in liver cells. Bioorg. Med. Chem. Lett. 14, 4975-4977.

Soutschek,J., Akinc,A., Bramlage,B., Charisse,K., Constien,R., Donoghue,M., Elbashir,S., Geick,A., Hadwiger,P., Harborth,J., John,M., Kesavan,V., Lavine,G., Pandey,R.K., Racie,T., Rajeev,K.G., Rohl,I., Toudjarska,I., Wang,G., Wuschko,S., Bumcrot,D., Koteliansky,V., Limmer,S., Manoharan,M., and Vornlocher,H.P. (2004). Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432, 173-178.