Saturday, May 16, 2015

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.


Anonymous said...

Asher has been on SMN-Rx since 7 months old.

How old is he and was he classified as a Type II?
1 · May 12 at 10:03pm

Arms for Asher - Fighting SMA Together Hi Kathy!Asher turned 2 in March. He is officially functioning as a type 2 now. When he was diagnosed at 6 months he did not sit up, crawl or roll over and he presented at 4 months so he was diagnosed a type 1. He was always on the stronger side because he had moderate head control, the ability to swallow and could move his arms.
1 · May 13 at 5:06pm
Asher has been in the ISIS clinical trial since 7 months old.

doesn't isis release study results soon?

Anonymous said...

You've been bashing
ADXS for quite some time but if one looks at recent published research, therapeutic vaccines combined with immune antibody modulators are showing very good results. You may eat crow here

Anonymous said...

SMA mom: Everyone knows it ( $ISIS) works and are just sitting and watching their children lose the ability to play with their toys @US_FDA

the only thing everyone knows is send more $...that's the only tune big pharma and the foundations know....where's the outrage?

Anonymous said...

Cancer charities accused of spending $187 million in donations on dating sites, trips to Disney

make you wonder......?

Anonymous said...

ask the FDA to "Be reasonable" and use accelerated approval for a whole class of new medicines

The parents of boys with Duchenne muscular dystrophy, or DMD are fighting the same battle we're fighting with the U.S. Food and Drug Administration. In this new campaign launched by, UCLA professors Dr. Stanley Nelson and Carrie Miceli, they ask the FDA to "Be reasonable" and use accelerated approval for a whole class of new medicines for DMD., they launched a social media campaign called "Be Reasonable" on May 9th.

We're asking Dr. Janet Woodcock for the same thing and that is to please "Be reasonable"!

GENE genie said...

Aptamers can be very rapidly sorted to specific targets using the library available which is also ex patent , the are good to deliver shRNA as well as SI, I don't understand why they are not used more , Prof Rossi prior to his stoke was about to focus on their use, I hope others rekindle interest in this most promising delivery approac

By Dirk Haussecker. All rights reserved.

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