The demonstration represents a significant advance in the development of the RNA interference (RNAi) technique. Systemic delivery through the bloodstream potentially enables RNAi therapeutics to target virtually any gene involved in the cause of human disease.

Lowered Blood Cholesterol Demonstrated

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.

"We have meaningfully advanced the field of RNAi in this first ever demonstration of RNAi mediated by systemically delivered siRNAs, providing tangible evidence of the broad potential for RNAi therapeutics," said Hans-Peter Vornlocher, Ph.D., Vice President of Research at Alnylam Europe AG.

Far-Ranging Possibilities

"This significant research is a major step forward as we seek to develop systemic RNAi therapeutics for the broad-based application of RNAi to important diseases such as cardiovascular disease, diabetes, obesity, hepatitis, cancer, and many infectious diseases," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam Pharmaceuticals.

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.