Nature, Volume 432, pp. 173-178.

November 2004, Alnylam scientists published a landmark article in the journal Nature that demonstrated the first systemically delivered RNAi-mediated gene silencing in vivo that potentially can be applied to systemic RNAi therapeutics for human disease.

In the published research, Alnylam scientists demonstrated in vivo silencing of the gene for apolipoprotein B (apoB), a protein involved in cholesterol metabolism, and the consequent reduction in blood cholesterol levels.

This specially engineered siRNA was able to reach and enter appropriate cells by incorporating proprietary chemical modifications that provided "drug-like" properties.

Intravenous injection of the modified siRNA into mice resulted in silencing of apoB messenger RNA (mRNA) in liver and intestine, and reduced blood levels of both apoB protein and total cholesterol.

Nature, Volume 438, pp. 685-689

In October 2005, Alnylam and scientists from Rockefeller University published in the scientific journal Nature a novel approach to regulate gene expression through the silencing of miRNAs. The publication describes the rational design of a potential new class of chemically modified RNA-based drugs, called 'antagomirs', that specifically silence miRNAs across multiple tissue types following therapeutically relevant administration in animals. The discovery of antagomirs represents the first-ever demonstration of pharmacologic strategy to silence miRNAs.

Nature, Volume 440, 206 (doi:10.1038)

In March 2006, Alnylam published, in Nature, the first demonstration in primates that a systemically delivered RNAi therapeutic can potently silence an endogenous disease-causing gene in a clinically relevant manner. This research represents a major advance because it suggests that an RNAi therapeutic can be effective when delivered systemically using a dosage appropriate for application in future human clinical studies.

In the study, Alnylam scientists and collaborators, Protivia Biotherapeutics, showed that systemic delivery in non-human primates of a chemically optimized small interfering RNA, or siRNA, can result in silencing of the apoB messenger RNA (mRNA), leading to significant reductions in blood levels of the apoB protein. These effects were proven to occur through an RNAi-mediated mechanism, and resulted in immediate, potent, and durable therapeutic efficacy.

Other Publications

Bitko, V., Musiyenko, A., Shuylaleva, O., Barik, S. Inhibition of Respiratory viruses by nasally administered siRNA. Nature Medicine 11, 50-55 (2005).

Hornung, V., Guenthner-Biller1, M., Bourquin1, C., Ablasser, A., Schlee, M., Uematsu, S., Noronha, A., Manoharan, M., Akira, S., de Fougerolles, A., Endres1, S. & Hartmann, G. Sequence-specific potent induction of IFN- by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nature Medicine 11, 263-270 (2005).

Bhandari1, V., Choo-Wing1, R., Lee, C. G., Zhu, Z., Nedrelow1, J., Chupp, G.L., Zhang, X., Matthay, M.A., Ware, L.B., Homer, R.J., Lee, P.J., Geick, A., de Fougerolles, A., & Elias, J.A. Hyperoxia causes angiopoietin 2–mediated acute lung injury and necrotic cell death. Nature Medicine advance online publication advance online publication 5 Nov 2006 (doi:10.1038/nm1494)

Nature Collections

RNA Therapy(September 2005).

Produced with support from Merck & Co., Inc and Alnylam Pharmaceuticals

Nature Insight

RNA Interference. Vol. 431, No 7006 (16 September 2004).

Produced with support from Merck & Co., Inc and Alnylam Pharmaceuticals