Harnessing the role of RNA in gene regulation

Thursday, 13 November 2014

The sequencing of the human genome and the rapid progress of technologies enabling its manipulation have led modern-day scientists to challenge the central dogma of molecular biology, that DNA makes RNA makes protein. In fact, current thinking indicates that genetic information can flow in both directions between DNA and RNA and far from playing an intermediary role, RNA is a pivotal means by which the genome can be altered. In line with these advances, RNA biology is a key research focus for therapeutic intervention at AstraZeneca, and one that complements our conventional approaches such as small molecule, protein engineering and antibody based therapeutics.

For many years, RNA was considered merely an intermediate molecule in the transcription of the genome, despite the fact that only about 5% of the transcribed RNA encodes for mRNAs that are translated into proteins. However, the significance of the remaining 95% of non-translated RNA (non-coding RNA) is now appreciated and we are gaining a better understanding of the role it plays in regulating the translation and function of proteins and how we might intervene in this regulation. For example, a growing legion of microRNAs are being generated that can modulate coding messenger RNAs via the RISC complex to inhibit translation of mRNA into protein (1). Other non-coding RNAs modulate the transcription of the DNA (2) and emerging evidence suggests RNA molecules can directly bind and modulate translated proteins(3)

Therapeutics targeting RNA offer enormous potential – not only can they be used to tackle the 80% of translated proteins that are difficult to modulate with either small molecule drugs or antibodies but can also be used to modulate the regulatory non-coding RNA. This opens up an enormous number of new targets for disease intervention and advances in RNA therapeutic chemistry to increase stability and potency are opening up a new wave of therapeutic molecules. Additionally, because RNA-directed drugs can be rationally designed based on the target sequence, RNA therapeutics offer significant advantages in drug discovery efficiency.

In 2012, AstraZeneca formed strategic collaborations with Regulus Therapeutics and with ISIS Pharmaceuticals to work on short 15-20mer oligonucleotides that could modulate microRNAs or RNA sequences encoding therapeutic proteins. These short, stable oligonucleotides can be administered systemically in saline, are distributed to a range of tissues and modulate the desired target. This research effort has made good progress and two therapeutic ologonculeotides are now in clinical testing with a number of others at various stages of the discovery pipeline.

A more recent deal in the RNA space with Moderna therapeutics was signed in 2013 looking to exploit full length modified mRNA as a way to generate therapeutic proteins in situ within the human body.

The selective delivery of oligonucleotides to specific tissues has the exciting potential to open up even more cell types to potent modulation by these molecules and improve their therapeutic activity. Both Regulus Therapeutics and ISIS Pharmaceuticals have developed GalNAc– oligo conjugates which specifically target a receptor on liver hepatocytes leading to a much higher percentage of RNA reaching these cells; the consequence is that approximately 10 fold lower therapeutic doses could be needed for hepatocyte microRNA or mRNA targets (4).

To build on this early success with RNA targeting, we are now joining forces with ISIS pharmaceuticals to develop additional targeting mechanisms to further improve oligonucleotide delivery to tumour cells and a number of cell types of interest for cardio-metabolic disease. We also launched an open innovation call on the AZ Open Innovation portal for solutions for oligonucleotide targeted delivery earlier this year. Over 500 scientists from around the world signed up to review the challenge and approximately 60 solutions were submitted for consideration. From these 4 are now being developed into work plans to test whether they offer additional solutions for specific delivery of oligonucleotides.

Thus, with the revelation that most of the information being transacted through the genome is conducted through RNA regulatory networks, it’s exciting times for RNA therapeutics. Like many new technologies, the field has taken over 20 years to mature but now it seems that RNA based therapeutics is within our grasp.


1. Condorelli G et al,microRNAs in Cardiovascular diseases: Current knowledge and the road ahead J Am Coll Cardiol 63, 2177-87, 2014

2. Bergmann JH and Spector DL, Long non-coding RNAs: modulators of nuclear structure and function. Curr Opin Cell Biology 26, 10-18 2014

3. Costello A et al, Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149, 1393-406, 2012

4. Prakash, Thazha P et al Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Research 42, 8796-807, 2014.