Shape and size matter when it comes to RNA interference
RNA interference, or RNAi, is a relatively young but important field of study in genetics research that is leading to new treatment options for cancer, diabetes, HIV/AIDS and other serious illnesses. City of Hope scientists recently published findings that may advance these efforts in the journal Nucleic Acids Research.
Study first author Nicholas Snead, Ph.D., a recent graduate of the Irell & Manella Graduate School of Biological Sciences at City of Hope, explains the significance of the study results that appear in the paper, titled “Molecular basis for improved gene silencing by Dicer substrate interfering RNA compared with other siRNA variants.”
What’s the main finding of this study?
The study revolves around a process in our cells called RNA interference, which is a way to suppress the level of any protein we want. We, as researchers, initiate RNAi by administering a small double-stranded RNA. Different researchers use different lengths and shapes of these small double-stranded RNA when initiating RNAi, with some researchers claiming that certain lengths and shapes work better than others. Most researchers, however, only look for the end-result of RNAi.
Our study focused on trying to understand some of the intermediate steps in the RNAi process with these differently shaped small double-stranded RNA. The main finding was that slightly longer and asymmetric double-stranded RNAs called Dicer substrate RNA (dsiRNA) — which were pioneered in Dr. [John] Rossi's lab several years ago — perform better than the "classically" shaped double-stranded RNAs in early, intermediate and late stages of the RNAi pathway.
What kind of impact do you expect the study findings to have?
RNAi's ability to suppress any protein we want is very powerful, not only for basic scientists but also for an emerging community of researchers trying to develop RNAi-based therapeutics. When developing therapeutics, we want to achieve the highest potency while minimizing unintended effects. Hence, by understanding why some small double-stranded RNA initiators work better than others, researchers can strive for the best therapeutic efficacy in the future.
From more of a basic science standpoint, our study provides a more comprehensive set of tests that researchers can do to really convince the community if a nonclassical RNAi initiator truly is the best.
What are the next steps for this line of research?
Several companies are already developing RNAi-based therapeutics, with a handful of studies in phase I or II clinical trials. For intellectual property reasons, some companies have their reasons for choosing certain RNAi initiators. But, for companies that still have the flexibility and resources to pick the best type of RNAi initiator, our study makes the case that the "classically" shaped double-stranded RNAs are not necessarily the best.
The research team included Xiwei Wu, M.D., Ph.D., Arthur Li, Qi Cui, Kumi Sakurai, John C. Burnett, Ph.D., and Rossi, all from City of Hope.
This work was supported by National Institutes of Health grant HL074704.