Editorial
RNAi Therapy Collection
In this special collection, we highlight papers published in Nature, Nature Medicine, and Nature Biotechnology that have contributed to the development of RNA interference, or RNAi, as a novel therapeutic modality.
When it was first found that short, non-coding RNA molecules could affect protein expression levels, it was immediately appreciated that this normal cellular process might be exploited as a therapy. For example, if a disease resulted from overexpression of a normal protein, or expression of a mutant protein, one might be able to use RNAi to reduce the levels of a specifi c protein to reverse or ameliorate its deleterious effect.
There are several practical barriers to using RNAi therapeutically. Two of these include delivery of the targeted small RNA to the cell, and protection or stabilization of the RNA molecule to degradation by nucleases. Initial studies of RNAi in vivo proved the underlying principle—that injection of small RNAs could downregulate protein levels from the targeted mRNA. By injecting such RNAs into the mouse tail vein, it was shown that this could prevent hepatitis (McCaffrey et al. 2002, 2003). These results were encouraging, but the mode of delivery was certainly not clinically relevant.
As an alternative means of delivery, viral vectors were used to introduce an RNA sequence into the cell which the host machinery then converted into short RNAs; this method was shown to suppress neurodegeneration in both spinocerebellar ataxia (Xia et al. 2004) and ALS (Raoul et al. 2005; Ralph et al. 2005) mouse models. More recently it was described how small RNAs can be chemically modifi ed so that they can be administered intravenously, remain stable in the bloodstream, and yet enter the cell to silence a gene involved in LDL formation (Soutchek et al. 2004). A newer method involves administration by nasal spray, to target respiratory infection (Bitko et al. 2005).
While many of such studies have not noted signifi cant non-specifi c (or off-target) effects, one strong concern has been the effect of RNA administration on the immune system. Whether this provokes an interferon response remains a controversial topic, however, as refl ected in confl icting recent reports (Heidel et al. 2004; Judge et al. 2005).
Other issues remain; notably, production of RNA on the scale required for therapeutic treatment remains prohibitively expensive. Yet RNAi-based treatments for various conditions are already undergoing clinical trials. We hope that future publications in the journals of Nature Publishing Group will illustrate the forefront of advances that bring us closer to resolving these remaining issues.
We are pleased to acknowledge the support of Alnylam Pharmaceuticals Inc. and Merck & Co., Inc. in producing this collection.
