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This was a good Nature article, thorough, well presented, and cleverly designed. The commentary by the journal on the article was also good providing both background, current relevance, and challenges both met and remaining.

RNAi has taken the target validation market by storm as an effective and easy to use technology to effect protein knockdown. It's success as a biotechnology 'tool' has inspired a few outfits to pursue potential therapeutic applications.

A comment on target validation before therapeutics . Target validation via protein knockdown technology is a screening method under which an endogenous protein is depleted, typically in a cell culture. RNAi works extremely well here. Simplistically, by depleting a protein one can in principal determine whether that protein plays a role in a significant cellular process and has potential as a drugable target. If the target is validated as a drugable target, rational drug design of small molecule inhibitors can be initiated.

The dominant players in RNAi for target validation are Ambion (private) and Dharmacon (acquired by Fisher Scientific – FSH in early 2004), primarily as providers of RNA based oligos. Other significant companies include Qiagen QGENF (Oligo purification), Invitrogen IVGN (labeling and transfection agents), and Promega. A good source of participating companies and product offerings can be found under the siRNA category at (something of a My Simon for the lab-geek set).

Anyway, the reason to pursue rational drug design vs. use the RNAi technology itself as a therapeutic is well described in the Nature paper. The issues with biological effect within the body is complicated by drug delivery and tissue distribution. Small molecules have a better shot at both. Antibody / protein based therapeutics try to boost or replace what is / should be already present in the bloodstream. Oligonucleotides are not normally freely circulating.

Alnylam was clever in recognizing that compounds with bad biodistribution tend to collect in the liver and kidneys, the organs of detoxification, and initially applying the RNAi technology a target (apoB) expressed within the liver can therefore be seen as an advantage. I am not sure this can be repeated for many more relevant targets. Additionally, RNAi technology will almost always be vulnerable to being submarined by a cheaper small molecule drug that inhibits the same target or pathway.

Both Alnylam (ALNY) and a competing company Sirna Therapeutics (RNAI) got a boost late yesterday, presumably on the Nature article. I would expect this to be somewhat short-lived.

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