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.
