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Scientists from Alnylam published today in Nature a paper discussing the effects of RNAi treatment on silencing apoB protein in mice. A significant portion of this data pertains to their delivery scheme for siRNA molecules into tissues.

http://www.nature.com/nature/focus/rnai/ has both the primary article and a review discussing the work, some of its implications, and a caution about its ability to be translated to humans. Both of these articles are posted on this site (the Web Focus) free of charge (for now).

If you're interested in RNA therapeutics, you may want to check this out.
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No. of Recommendations: 5
wpdolan

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.

http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v432/n7014/full/432155a_fs.html

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 Biocompare.com (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.

Fool on

ZuZuFool
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I haven't read the article yet but would like to comment on some of your Zuzufool's statements:

<<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.>>

They picked apoB because for decades nobody could find a small molecule to inhibit it (and many tried). Also Isis has presented some data using antisense to block apoB (from their Q3 report):

In August 2004, Isis reported preliminary data from a Phase 1 trial of ISIS 301012, a second-generation antisense inhibitor of apoB-100, at the 9th Drug Discovery Technology World Congress in Boston. ISIS 301012 produced dose-dependent, rapid and prolonged reductions of its target, apoB-100, in low density lipoprotein (LDL), very low density lipoprotein (VLDL) and total cholesterol levels in normal volunteers with borderline elevated cholesterol. ApoB-100 is the molecular carrier of LDL and VLDL cholesterol, the "bad" cholesterol involved in heart disease.

Isis and Alnylam have a collaboration:

Isis Pharmaceuticals Forms Strategic Alliance With Alnylam Pharmaceuticals in RNAi Therapeutics
Isis and Alnylam Bring Together Leading RNAi Patent Estates and Expertise to Develop RNAi Therapeutics
3/11/2004 4:05:00 PM

<<I am not sure this can be repeated for many more relevant targets.>>

I haven't heard anything about the PK of RNAi yet but maybe we get a surprise. Nobody planed to use Viagra the way it's used nowadays.

<<Additionally, RNAi technology will almost always be vulnerable to being submarined by a cheaper small molecule drug that inhibits the same target or pathway.>>

That statement IMHO is plainly wrong. With this mindset Amgen and Genentech and many other companies wouldn't exist, i.e no protein based
drugs. Gotta take some risks and try something new.

Santa

(posted w/o proof-reading, hope it's not too confusing)
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Also worth noting on the RNAi therapeutic front - Acuity Pharmaceuticals, a private company in PA, is going into clinic with an siRNA based drug candidate.

See press releases

http://www.acuitypharma.com/page4.html

I still like this technology better as a research tool than a therapeutic.

ZuzuFool
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