Less Is Sometimes More: Roche Brain Shuttle Technology for Drug Delivery into CNS

After Roche and ISIS Pharmaceuticals announced last April that a co-development effort to apply Roche’s Brain Shuttle technology for the systemic delivery of antisense oligos would form part of their Huntington’s collaboration, I started to pay some attention to this technology.  This is because despite the already enormous promise of Oligonucleotide Therapeutics for CNS disorders (think of all the neurodegenerative diseases) with the direct administration of single-stranded oligonucleotides into the CNS, its value could be further enhanced with a systemic delivery approach such as the Brain Shuttle tech.

This is not only because intravenous administration methods would be preferable over the more invasive direct intra-CNS injections/infusions, but also because a systemic delivery approach promises a more uniform drug distribution and would minimize the importance of diffusion.  It is the limited diffusion of current RNAi delivery techs that is holding back RNAi Therapeutics in this important therapeutic area.

Monovalent antibody binding to transferrin receptor allows for efficient transcytosis

The fundamental principle behind Brain Shuttle is actually not that novel at all. Companies like Armagen have long attempted to target receptors such as the insulin receptor and the transferrin receptor on brain capillary endothelial cells as in normal physiology these receptors function to shuttle transferrin/iron and insulin across the notoriously recalcitrant blood-brain-barrier.

Based on newly published data by Roche scientists (Niewoehner et al. 2014), a conventional antibody approach does not work.  To wit, a conventional antibody consists of two binding sites (divalent) and such engagement apparently causes receptor trafficking to be re-directed to the degradative lysosome compartment of the brain endothelial cells, at least in the case of the transferrin receptor tested.  By contrast, when receptor targeting occurs via monovalent interaction, the normal receptor physiology, including transcytosis, is maintained.  Using this strategy, it was shown that the intra-parenchymal delivery, i.e. delivery into the brain proper, of an antibody against beta-amyloid (related to Alzheimer’s disease) that had been tethered to the monovalent transferrin receptor antibody was enhanced on the order of 50-fold.

The way how this research can be translated into RNAi Therapeutics is to simply append an RNAi trigger instead of the beta-amyloid antibody to the transferrin receptor antibody.  Or you could do away with proteins altogether and replace the transferrin receptor antibody with an aptamer-RNAi trigger combo (e.g. a Dicer-substrate in the spirit of tomorrows IPO by Dicerna Pharmaceuticals).  Hence, the irony of the ISIS-Roche delivery collaboration is that ISIS could- to put it just slightly hyperbolically- be shoveling its own grave by eroding the current advantage of phosphorothioate antisense over RNAi for gene knockdown in the CNS.