Landmark Chemical Modification Study Shows RNA Editing Ready for the Clinic

At this stage, providing investors and the pharmaceutical industry with a clear line of sight that RNA Editing can be readily translated from concept into therapeutic reality is key to unlocking the next step-up in valuation.

A landmark study in March earlier this year by scientists from Wave Life Sciences (Monian et al, Nature Biotech) on chemically modifying ADAR guide RNA oligos (I will abbreviate them from now on AgRNAs due to missing consensus nomenclature) should go a long way in this regard.  It shows that applying a plethora of standard oligonucleotide stabilization chemistries (e.g. PS, PN backbones, 2’-O-methyl-, 2’-F-ribose) which are critical to enabling delivery and desirable durability do not compromise endogenous ADAR enzyme activity.

In fact, backbone stabilization for example via phosphorothioates, especially when in the SP stereopure conformation can actually greatly increase activity.  In a luciferase model system, editing activity of a fully (stereorandom) PS-modified AgRNA was 10x that of a corresponding AgRNA with an unmodified PO backbone.

Accordingly, when GalNAc-conjugated AgRNAs were tested in non-human primates, ~40% editing rates were observed for at least 2 months.  For this, a loading dose of 5mg/kg per day for 5 days was used.  This is on the higher end of what should be clinically acceptable, but as we know from experience with RNAi, what GalNAc works in non-human primates works even better in humans.

Illustrating the value of further refined chemical optimization of high-value candidates, impressive ~70% mRNA editing efficiencies were seen for a AgRNA against mutant SERPINA1 in primary mouse hepatocytes resulting in a concomitant increase in corrected protein.  SERPINA1 is also the target for Wave’s and possibly the industry’s first clinical RNAEditing program and addresses alpha-1-antitrypsin liver and lung disease.

What piqued my interest was that this AgRNA involved a 8-oxo-deoxyadenosine mismatch base opposite the adenine to be modified and a nearby inosine.  What this means will be addressed in my next blog entry...

So congratulations Wave Life Sciences on this study, but also they will admit that the study still only scratches the surface of what gains in potency will be possible with more detailed structure-activity studies.