Alnylam overcomes delivery problem with RNAi
Alnylam Pharmaceuticals has claimed a first with the publication of
a study showing in vivo RNAi-mediated gene silencing in
mammals by a method that potentially can be applied to systemic
RNAi therapeutics for human disease.
The research, published in Nature, represents a significant advance in the development of systemic RNAi therapeutics, according to the comany. Systemic delivery through the bloodstream potentially enables RNAi therapeutics to target virtually any gene involved in the cause of human disease, opening up the prospect for broad application of RNAi therapeutics to treat a wide range of diseases.
In the published research, Alnylam scientists demonstrated in vivo silencing of the gene for apolipoprotein B (apoB), a protein involved in cholesterol metabolism, and a consequent reduction in blood cholesterol levels. This was achieved using a specially engineered short interfering RNA (siRNA) that was given intravenously by a clinically relevant route of administration.
siRNAs are the molecules within cells that trigger RNAi. To enable the synthetic siRNA used in the study to reach and enter appropriate cells, this siRNA incorporated proprietary chemical modifications designed to provide it with "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. In parallel experiments, the ability of siRNAs to silence the human apoB gene in a transgenic mouse model was also demonstrated. The apoB gene is highly relevant clinically and to date has not been amenable to targeting with traditional small molecule, protein, or antibody therapies.
Hans- Peter Vornlocher, vice president of research at Alnylam Europe, noted that specific cleavage of the apoB mRNA at the predicted site was demonstrated in the study, and this confirmation of the specific mechanism of action of siRNAs "reinforces their therapeutic potential to harness the natural catalytic process of RNAi for the treatment of disease."
RNA interference, or RNAi, is a naturally occurring mechanism within cells for selectively silencing and regulating specific genes that is potentially the basis for a new class of therapeutic products. Since many diseases are caused by the inappropriate activity of specific genes, the ability to silence and regulate such genes selectively through RNAi could provide a means to treat a wide range of human diseases.
The discovery of RNAi has been heralded by many as a major breakthrough, and the journal Science named RNAi the top scientific achievement of 2002, as well as one of the top ten scientific advances of 2003.
