I wrote about Alnylam’s recent clinical disaster here, where they had to stop a Phase III siRNA therapy trial against a rare amyloidosis with cardiac complications. A reader sends along the link to this 2008 paper that suggests a possible reason for the excess deaths seen in the trial. The authors studied a range of different siRNA constructs in mice, and found that (as you’d expect and/or hope) that sequences targeting genes for VEGF inhibited vascularization. That’s what that growth factor is for (among other things), so that’s fine.
The problem, though, is that they found that pretty much everything else they tried (siRNAs for both pro- and antiangiogenic genes, for totally unrelated genes, for things that don’t even match a target at all) also showed these effects. This was one of the results from this period that alerted people to the effects of some siRNA agents on TLR3 signaling, which is one of the sensors of foreign RNA (and thus of infection). Human endothelial cells most definitely express TLR3, so (as the paper put it), you could say that siRNAs, even untargeted siRNAs, might be a clinically useful antiangiogenesis agent, or (alternatively), if you’re trying to target something else, you might be asking for vascularization side effects that you don’t want.
These concerns complicated the development of bevasiranib and AGN-745/Sirna-027 (both siRNAs directed at VEGF), but it does have to be noted that neither of them was associated with any severe side effects (rather, the bigger problem seemed to be efficacy). That said, these were injected directly into the eye compartment, so the possibility of systemic effects was probably minimal in any case. Overall, though, many suspect that what efficacy the first wave of siRNA clinical agents had may well have been due to this nonspecific TLR activation, and this was something that the field had to overcome.
VEGF effects would certainly seem to be something you’d want to look out for in patients that are already showing cardiac damage, but what I don’t know is the degree to which Alnylam’s GalNAc conjugate siRNAs (like revusiran) activate the TLRs. This seems like an issue that would have been publicly addressed, but I’m having trouble putting my finger on anything that directly does so. Perhaps it was dealt with right up front, and I’m missing it, but if anyone who follows the RNA therapeutics world more closely than I do can shed some light on this, I’d be glad to put up some links. . .