On the coming age of siRNA drugs

You all know what siRNAs are. Short, double-stranded RNA molecules that can regulate gene expression in a site-specific manner. Along with their various other natural and engineered counterparts (shRNAs, miRNAs, pi RNAs) it is anticipated that these reagents can be engineered to be effective drugs. Of course, we’ve been promised this before, in the guise of antisense oligonucleotides, which appeared not to pan out so well (but now are panning out surprisingly well; check out the ability of antisense oligonucleotides to alter splicing patterns and restore the function of mutant dystrophins in humans). In some ways, siRNAs can be thought of as son (or daughter) of antisense, but with greater potency because of the natural machinery that brings their base-pairing capabilities to bear.

The chief problem is delivery, as was the case for antisense oligonucleotides before them. You can ensconce them within liposomes or other lipid amalgams, you can tether them to delivery moieties like cholesterol, you can make peptide or protein complexes, you can even just rely on naked targeting and uptake (see the wonderfully named ‘gymnosis’ for details). These methods all have advantages and disadvantages, and there will doubtless be winners or losers in the end. But something will win. We will have sequence-specific gene modulation. And then it is hoped that the promise of molecular medicine originally seen in antisense oligonucleotides will be realized. We’ll be able to treat any disease, certainly any pathogen, by modulating gene expression in a sequence-specific manner.

But as a child of the 60s I have to wonder: what is the recreational potential of siRNA? Can we get down with them? And I have to answer: yes. Yes we can.

As an only mildly illicit example, there is a gene called MyoD that regulates muscle development. And there is a very interesting case of a small child in Germany who was born with a mutation in the MyoD gene. He was known locally as ‘Hercules,’ and for good reason. The kid was huge. At age 3 his limbs bulged with muscle. Now, imagine achieving the same effect by artificially knocking down the expression of MyoD, a single gene, with anti-MyoD siRNAs (again, assuming that the gnarly delivery problem is conquered). I have often suggested to my laboratory if research funding gets really tight we’re going to make up a big ol’ batch of the stuff, march down to the stadium, and make damn sure that our boys are much bigger than the OU players … for a profit, of course.


- originally posted on Friday, July 9th, 2010