Aptamer-Targeted RNAi Trigger Delivery

In honor of 25 years of aptamers, or better the SELEX process which underlies the discovery of aptamers, I thought it might be a good time to revisit aptamers for the delivery of RNAi Therapeutics.

Aptamers are nucleic acids that have been selected to preferentially recognize a target, usually a protein, via their 3-dimensional structure in analogy to how monoclonal antibodies recognize their targets.  Aptamers are showing most promise in therapeutic development for the targeting of extracellular proteins in the eye for applications like wet AMD and diabetic macular edema (see Fovista from Ophthotech). 

Its success for systemic applications has been much more modest, however, with short circulation times and unexpected adverse events in a recent phase III study (likely due to the PEG portion of the aptamer drug) largely accounting for it.

Aptamers have also been considered as cell-targeting agents for RNAi Therapeutics.  Early reports suggested efficacy in HIV and cancer models.  Skepticism around the on-target mechanism in these examples was considerable though largely due to questions around how they were supposed to escape the endosomes.

I also fell into the camp of doubters (and still have some reservations), but have adjusted my view to a more productive one after it became clear that IF you had highly productive endosomal uptake like ASGPR/GalNAc and a highly stabilized RNAi trigger, gene silencing is possible even without explicit endosomal release chemistry.

Time to try the next iteration: Aptamer-DPCs

As there may not be another ASGPR-type receptor in the body and to compensate for lower drug exposure compared to the liver, in the quest to make aptamer-delivered RNAi Therapeutics more robust, the new learnings of RNAi trigger stability are probably best applied within the context of DPC delivery technology by Arrowhead Research.

Accordingly, the perhaps 10x lower uptake in say PSMA-expressing prostate cancer cells will be compensated by adding the RNAi trigger-aptamer complex (as one or separately) to a masked endosomal release polymer.  In case that the target cell receptor is only abundant, but does not support productive endosomal uptake, another aptamer may target a second co-receptor on the same cell (akin to some bispecific antibodies, co-receptors in viral cell uptake).

Following endosomal uptake, the masking groups come off, endosomal permeability increased so that the RNAi trigger may escape into the cytoplasm.  In certain configurations, a Dicer substract-type RNAi trigger structure may simplify design and increase stability.