RNAa
RNA activation (RNAa)
RNA activation, or RNAa, represents our dedication and scientific leadership in the ever expanding field of RNA therapeutics.
In an opposite manner to RNAi technology where specific genes are inhibited, RNAa technology results in the activation of gene expressionand has potential applications in certain genetic diseases and cancer. Recent work from the labs of Dr. Corey at UTSW and Dr. Li at UCSF has given us clearer mechanistic insights into this emerging biology. RNAa is mediated by double-stranded RNAs called "anti-gene RNAs" or "agRNAs" that are designed to be complementary to certain promoter regions of chromosomal DNA and have been found to significantly and reproducibly activate transcription of DNA to RNA by nearly 10-fold. This could be used to activate gene expression in a pharmacologically relevant manner, in contradistinction to RNA interference, which silences gene expression. While there's more to do here, RNAa technology could represent a new product platform in Alnylam's efforts to advance innovative medicines to patients, and we look forward to seeing how this progresses in the future.
Studies to date
In in vitro studies, agRNAs have been shown to increase the levels of a target gene's mRNA by nearly 10-fold, resulting in an increased level of the target gene's protein. The work by the Corey lab at UT Southwestern for the activation of the progesterone receptor was published in 2007 (Janowski et al., Nature Chemical Biology 3, 166-173 (2007)) and a potential mechanism for RNAa is highlighted in a more recent paper (Schwartz et al., Nature Structural & Molecular Biology, doi:10.1038 / nsmb.1444(2008)). In addition, studies on RNAa have been performed by the Dahiya and the Li labs at UCSF (Li et al., PNAS, 103, 17337-17342 (2006); Chen et al., Mol Cancer Ther 7, 698-703 (2008); and Place et al., PNAS, 105, 1608-1613 (2008)) with a range of activated genes including VEGF, E-cadherin, and p21, as well as by the Gage lab (Kuwabara et al., Cell, 116, 779-793 (2004)) at the Salk. While additional work is necessary to understand the breadth of this biology, its applications in vivo, and its potential as a pharmacologic strategy, activation of gene expression with RNAa could offer new approaches for innovative medicines.
