(Almost*) First Clinical Trial with RNA Aptamers

Check this out:

First-in-Human Experience of an Antidote-Controlled Anticoagulant Using RNA Aptamer Technology

From the paper:

A translatable platform for developing an optimal parenteral anticoagulant should consider several prerequisite properties: easy delivery, rapid onset of action, and predictable responses among the dose, pharmacokinetic profile, and pharmacodynamic effects to reduce the requirement for routine monitoring. Additionally, an optimal anticoagulant should be biologically selective and actively reversible.

What is in use currently?

Unfractionated heparin is currently the only antidote-reversible anticoagulant. Despite its wide-scale use, unfractionated heparin suffers from a number of well-described and clinically relevant limitations: Its complex pharmacokinetics make dose selection and titration difficult and imprecise5; the effective use of its antidote, protamine sulfate, shares similar unwanted complexity, dose-response variability, and has the potential to elicit serious cardiovascular side effects6,7; and perhaps of greatest concern, heparin compounds can cause a limb- and life-threatening drug-induced, immune-mediated syndrome known as heparin-induced thrombocytopenia.8

And so, why not use an RNA molecule that can bind to the one of the plasma proteases participating in coagulation, such as thrombin. BTW RNAs that can bind to stuff = RNA aptamers. In this case the aptamer (RB006) can bind and thus inactivate coagulation factor IXa.

RB006 elicits an anticoagulant effect by selectively blocking the factor VIIIa/IXa-catalyzed conversion of factor X to factor Xa, a pivotal step in prothrombinase assembly and thrombin generation on the surface of tissue factor-bearing cells and activated platelets.

As you can see, the activity of this aptamer can readily be reversed with the use of an antisense RNA oligo (RB007) - (nice name for an "agent" ...)

Now of course these RNAs can't be administered orally. But they can be injected into the blood system. And blood does have some nucleases, so the compound had to be stabilized by modifying the two ends (see pic - P = polyethylene glycol; idT = inverted deoxythymidine.)

Very cool stuff. [HT: BC]

Christopher K. Dyke et al.
First-in-Human Experience of an Antidote-Controlled Anticoagulant Using RNA Aptamer Technology
A Phase 1a Pharmacodynamic Evaluation of a Drug-Antidote Pair for the Controlled Regulation of Factor IXa Activity
Circulation (06) 114: 2490 - 2497

*-Sean Eddy points out in the comment section that there is already an FDA aproved aptamer - Macugen, aka pegaptanib. It's an aptamer that binds and inhibits VEGF (link).

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I think they mean 'first' in a more specific sense. There's already an FDA-approved drug on the market that's an RNA aptamer: Macugen, for treating wet macular degeneration.

By Sean Eddy (not verified) on 24 Dec 2006 #permalink

I appreciated the drug-antidote concept the orginal investigators incorporated into the project. Good stuff.

To spread some holiday cheer around, I wonder what other people think of the patent over aptamer technology? It's owned by Archemix at this point. I wonder if people view owning aptamer technology in totality (other than the couple of aptamers that were developed prior to the patent award) as different than patenting a gene or a set of genes?


If that's true it's horrible. The raison d'etre for patents is to encourage technology developement, this type of patent can only disuade research into new aptamers. Not that science in aptamer technology will stop, but it just became a lot less profitable for pharama and other biotech companies.

My data point is talks with key a key scientific advisory board member of the company - they bought it from Gold's company, Gilead, IIRC (see wikipedia's aptamer page).

There are small companies such as Q-RNA that are based specifically on a single aptamer or class of aptamers (not clear to me from QRNA's site) and if they didn't get grandfather'ed then I'd say they're at the mercy of the patent holder.

I don't have the answer to the patent problem, but I do think it's a problem and that with some creativity and effort, a solution could be developed that all parties (the public vs those with a vested financial stake in a particular gene patent or technology patent such as aptamers) could accept.

Me and my colleagues authored one of India's most extensive reports on clinical trials. Drop me a mail if you are interested in a copy. My email is ntaluk@gmail.com.

Some of the topics we included are:

- Market Trends
- Growth Drivers
- Regulatory Bodies and Framework
- Major Players.
We interviewed over 200 individuals and firms to collect the data in what we believe is one of the most detailed study on the subject in India.