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UT's Andrew Ellington on Using Aptamers to Deliver siRNAs

Name: Andrew Ellington
Position: Professor, chemistry/biochemistry, University of Texas at Austin
Associate professor, chemistry/biochemistry, University of Texas at Austin — 1998-2001
Associate professor, chemistry, Indiana University — 1992-1998
Research fellow, genetics, Harvard Medical School — 1988-1991
PhD, biochemistry/molecular biology, Harvard University — 1988
BS, biochemistry, Michigan State University — 1981

At the University of Texas at Austin, Andrew Ellington is developing functional RNAs that can be used in diagnostic or therapeutic applications. Part of his work involves the selection of binding species, or aptamers, and their use therapeutically and diagnostically.
At Beyond Genome 2007 last month in San Francisco, Ellington outlined the potential of aptamers for delivering siRNAs. He also co-founded a company aiming to commercialize the aptamer technology.
Other co-founders of the company, B3 Biosciences, include Duke University School of Medicine investigator Bruce Sullenger and executives from the biopharmaceutical firm Trimeris.
Last week, RNAi News spoke with Ellington about his work and the new company.
Could you give an overview of aptamers and how they apply to drug delivery?
Some time ago it was discovered by a variety of folks — including Larry Gold who was then at the University of Colorado, Boulder, and Jack Szostak who is at Mass General Hospital — that you could select functional nucleic acids from random sequence populations. In particular, you could select for binding function … and the binding species were called … aptamers.
You can actually find aptamers against a wide variety of targets, [and] they typically bind their targets with Kd values down in the nanomolar range. Interestingly, because the process is completely in vitro, you can select against complex targets such as cells. Because of that, it was hypothesized early on … that aptamers might act in an escort capacity; that is, they might be able to take other compounds to a cell, based on their ability to bind to a cell or target.
What Bruce [Sullenger] and I have recently shown was that a particular aptamer that targets a cell-surface protein, an anti-prostate-specific membrane antigen … could be used to localize various things at the cell surface and actually be endocytosed.
I showed that you could actually carry across a toxin, and Omid Farokhzad, who is in Bob Langer’s lab at [the Massachusetts Institute of Technology], showed that you could carry across nanoparticles.
Then, Bruce and I both showed that you could carry siRNAs across [into the cell].
And these were in tumor cells?
Yeah. A line called LNCaP, [which] expresses prostate-specific membrane antigen on its surface, so the aptamer binds to PSMA and then is internalized. What [neither] Bruce nor I necessarily thought would occur was that after what we presume is endocytosis, the aptamers and their cargo then become available to the processing machinery for loading onto RISC.

That was a bit of a surprise … but great in that it allowed us to do functional delivery of siRNAs and do knockdowns in these tissue cultures.

So you were able to achieve knockdown of specific targets.
That’s right. And the cool thing is that you don’t need a liposome. I have nothing against liposomes and nothing against nanoparticles and nothing against other delivery methods, but there is a certain advantage to saying, ‘All I’m going to do is synthesize one RNA or a couple of RNAs and hybridize them to one another, then use that as my delivery vehicle.’
In some ways, it’s the ultimate nanoparticle — it’s the molecule having both a delivery and a pharmaceutical functionality in the same batch.
Given that it is not encapsulated, what does that mean as far as stability?
The aptamers actually contain 2-fluoro pyrimidine residues, which substantially stabilizes them, even in inclement environments such as the serum. So they’re stable to nuclease degradation for upwards of two days.
Now, the siRNAs themselves might be a little more susceptible to degradation, but the uptake process is very fast. So I would imagine that if you had an injectable and circulating material — assuming that it made it to its target, which is a different pharmacokinetic question — it would be quickly taken up and there would be very little opportunity for the aptamer or the siRNA to degrade. You’d probably get a great deal of functional molecule on target and loaded.
Is the potential for systemic delivery [of RNAi-based drugs] using this approach?
We think so, and that’s something we’re working hard on. … We believe we can craft nucleic acids with distinct pharmacokinetic properties, and part of the technology we’re hoping to roll out as B3 Biosciences is not just targeting to biomarkers or cell surfaces, but in fact targeting within the organisms as a whole.
Has work been conducted trying to target other types of cells and tissues?
Work has been conducted, but nothing that we’re ready to talk about.
B3 Biosciences — what stage of development is that in?
Having set down what we believe is key intellectual property, we’re in the process of acquiring our initial funding. Bruce and I are both well-funded from government sources, and the technologies continue to be developed at a rapid pace, but obviously we’d like to begin to roll it out into a more commercial venture and to focus on commercial endeavors as soon as possible.
So IP has been filed, and [you and Bruce] have licensed it from your respective institutions?
Licensing negotiations with Duke and UT are both well along.
Where does the name B3 come from?
It comes from the fact that there were originally three founders: Bruce [Sullenger], [Trimeris CEO and CSO] Dani Bolognesi, and [Trimeris CFO] Bob Bonczek. They were the three Bs. I came along later, but they had already called it B3. … It’s really B3 plus A, but we’re going to leave the A off of the name for right now.
So you envision B3 being a drug-delivery company?
A lot of those kinds of questions will be answered along with the financing. Investors have a way of saying what they want the company to be. But from my perspective, the company has a two-pronged strategy.
Bruce has also developed a number of aptamer agonists that can activate receptors. My lab also works on the development of anti-protein aptamers. So pure aptamer technology that can be used in vivo for immune stimulation or for causing other physiological changes, we think, can and should be part of the company. Beyond that, it will be for the development of delivery platforms.
In my opinion, if we develop a good delivery platform, there are any of a number of buyers for that platform. The delivery of siRNAs, and beyond those, microRNAs, is a key impediment to the utilization of those molecules as therapeutics. While there are certainly a number of delivery strategies out there, we believe ours will be competitive in a variety of ways — most notably in the quality control of the molecules that are produced, cGMP manufacture, cost of goods, and eventually I think [aptamers] will prove to be superior in terms of pharmacokinetic properties.
Aptamers or nucleic acid delivery agents are going to be very small. They’re going to be able to penetrate into portions of the vasculature that even nanoparticles might find difficult to reach.
How small are we talking?
We’re talking basically an entire delivery moiety and payload of somewhere under 40 kilodaltons.

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