In recent years, readers of the top-tier journals have been bombarded with papers on nanotechnology as a possible means of drug delivery. At the same time, there's been a tremendous amount of time and money put into RNA-derived therapies, trying to realize the promise of RNA interference for human therapies. Now we have what I believe is the first human data combining both approaches.
Nature has a paper from CalTech, UCLA, and several other groups with the first data on a human trial of siRNA delivered through targeted nanoparticles. This is only the second time siRNA has been tried systemically on humans at all. Most of the previous clinical work has been involved direct injection of various RNA therapies into the eye (which is a much less hostile environment than the bloodstream), but in 2007, a single Gleevec-resistant leukaemia patient was dosed in a nontargeted fashion.
In this study, metastatic melanoma patients, a population that is understandably often willing to put themselves out at the edge of clinical research, were injected with engineered nanoparticles from Calando Pharmaceuticals, containing siRNA against the ribonucleotide reductase M2 (RRM2) target, which is known to be involved in malignancy. The outside of the particles contained a protein ligand to target the transferrin receptor, an active transport system known to be upregulated in tumor cells. And this was to be the passport to deliver the RNA.
A highly engineered system like this addresses several problems at once: how do you keep the RNA you're dosing from being degraded in vivo? (Wrap it up in a polymer - actually, two different ones in spherical layers). How do you deliver it selectively to the tissue of interest? (Coat the outside with something that tumor cells are more likely to recognize). How do you get the RNA into the cells once it's arrived? (Make that recognition protein is something that gets actively imported across the cell membrane, dragging everything else along with it). This system had been tried out in models all the way up to monkeys, and in each case the nanoparticles could be seen inside the targeted cells.
And that was the case here. The authors report biopsies from three patients, pre- and post-dosing, that show uptake into the tumor cells (and not into the surrounding tissue) in two of the three cases. What's more, they show that a tissue sample has decreased amounts of both the targeted messenger RNA and the subsequent RRM2 protein. Messenger RNA fragments showed that this reduction really does seem to be taking place through the desired siRNA pathway (there's been a lot of argument over this point in the eye therapy clinical trials).
It should be noted, though, that this was only shown for one of the patients, in which the pre- and post-dosing samples were collected ten days apart. In the other responding patient, the two samples were separated by many months (making comparison difficult), and the patient that showed no evidence of nanoparticle uptake also showed, as you'd figure, no differences in their RRM2. Why Patient A didn't take up the nanoparticles is as yet unknown, and since we only have these three patients' biopsies, we don't know how widespread this problem is. In the end, the really solid evidence is again down to a single human.
But that brings up another big question: is this therapy doing the patients any good? Unfortunately, the trial results themselves are not out yet, so we don't know. That two-out-of-three uptake rate, although a pretty small sample, could well be a concern. The only between-the-lines inference I can get is this: the best data in this paper is from patient C, who was the only one to do two cycles of nanoparticle therapy. Patient A (who did not show uptake) and patient B (who did) had only one cycle of treatment, and there's probably a very good reason why. These people are, of course, very sick indeed, so any improvement will be an advance. But I very much look forward to seeing the numbers.