Silencing genes with RNA interference has reduced cholesterol levels in mice in a significant step towards human use.

RNA interference, discovered quite recently, is a process that stops the translation of genes into proteins. It has attracted much attention as a possible method of gene therapy. Using it for this purpose, however, has presented challenges relating to the delivery of pieces of interfering genetic material.



Researchers at Cambridge, Massachusetts-based Alnylam Pharmaceuticals have now reported on a successful RNA interference therapy that nearly halved cholesterol levels in mice. This is the first time that such a therapy has been successful in animals, and is considered an important step towards using RNA interference to treat diseases in humans.


“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,” says Alnylam CEO John Maraganore.



RNA interference occurs when pieces of genetic material called short interfering RNAs (siRNAs) disrupt the production of proteins. The process is thought to have evolved as a defense against viruses, but cells also use it to regulate genetic activity.


Getting siRNAs into cells to treat disease has proven to be difficult, as they tend to be damaged or destroyed along the way.


Alnylam researchers addressed this problem by joining specially engineered siRNAs to molecules of cholesterol. The siRNAs target apolipoprotein B, an important protein for cholesterol’s production.


Through their proprietary technique, the researchers got siRNAs to bind to proteins in blood and increased their stability 15 times. The cholesterol molecule also allowed the siRNAs to get inside cells.



Mice injected with the treatment had levels of apolipoprotein B drop nearly 70%. Their cholesterol levels also dropped dramatically, to similar levels as animals that had the apolipoprotein B gene deleted entirely.



The treatment approach is considered clinically relevant because RNA interference therapies delivered through the bloodstream could target virtually all genes responsible for human diseases.



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