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Fooling Brain Defenses to Deliver an Alzheimer’s Drug

The views expressed are those of the author and are not necessarily those of Scientific American.

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Futile Gesture: Like this woman at the Berlin Wall, pharma companies have been able to do little more than wave across a formidable barrier when developing neuro drugs.

The blood-brain barrier is the Berlin Wall of human anatomy and physiology.

Its closely packed cells shield neurons and the like from toxins and pathogens, while letting pass glucose and other essential chemicals for brain metabolism (caffeine?).

For years, pharmaceutical companies and academic researchers have engaged in halting efforts to traverse this imposing blockade in order to deliver some of the big molecules that might potentially help slow the progression of devastating neurological diseases.

Like would-be refugees from the former East Germany, many medications get snagged by border guards during the crossing—a molecular security force that either impedes or digests any invader. There have been many attempts to secure safe passage—deploying chemicals that make brain-barrier “endothelial” cells shrivel up, or wielding tiny catheters or minute bubbles that slip through minuscule breaches. Success has been mixed at best—none of these molecular cargo carriers have made their way as far as human trials.

Roche, the Swiss-based drugmaker, reported in the Jan. 8 Neuron a bit of progress toward overcoming the lingering technical impediments. The study described a new technique that tricks one of the BBB’s natural checkpoints to let through an elaborately engineered drug that attacks the amyloid-beta protein fragments that may be the primary culprit inflicting the damage wrought by Alzheimer’s. The subterfuge involves the transferrin receptor, a docking site used  to transport iron into the brain. Roche took a fragment of an antibody that binds the transferrin receptor and latched it onto another antibody that, once on the other side of the BBB, attaches to and then removes amyloid.

This strategy has been tried before, but the molecule, once through the gate, is often consumed by the lysosome, a cellular garbage disposal system. That’s where the trickery comes in. Roche’s Brain Shuttle, as it is called, uses only one instead of both arms of the upper structure of a Y-shaped antibody that binds to the transferrin receptor—making it a monovalent instead of a bivalent antibody. That design, similar to the molecular structure of the natural transferrin protein that attaches to the receptor, seems to allow unhindered passage. Using this approach, the company reports that the other part of the drug, the antibody that attaches to the the amyloid target, does so 55 times better than if a bivalent antibody had been used or an anti-amyloid antibody alone.

Roche intends to make the Brain Shuttle an all-purpose, military-style transport for carrying big molecules into the brain and has struck agreements with two partner companies to attempt to use the molecular shuttle for carrying drugs to treat Huntington’s and Parkinson’s

All of this is still a work in progress. One start-up company that is also developing cellular Trojan Horses has doubts about the prospects for the Brain Shuttle.”The Roche paper would lead the reader to believe that a bivalent transferrin receptor monoclonal antibody (TfRMAb) does not work,” says William Pardridge, a UCLA professor emeritus and founder of a company called ArmaGen Technologies in Santa Monica, that  is developing a BBB transit system.  “…We have published over 10 papers in the last three years with a high affinity bivalent transferrin monoclonal antibody showing pharmacologic efficacy in experimental Parkinson’s, lysosomal storage disease, and stroke, as well as AD.” Pardridge also questioned the methods used by Roche, characterizing them as “non-quantitative measures of brain uptake.”

Per-Ola Freskgård, a leader of the Roche team that authored the study, defended the technical methods detailed in the paper and  fired back his own critique of one of Pardridge’s studies, saying it  lacked any data about how much of the  drug actually reached the amyloid plaques, an amount that, if it tracked closely Roche’s own testing of bivalent antibodies, might have been nil.

These arguments are not going to be resolved with a coach’s challenge—and it may be a while before BBB transporters enter the standard pharmacopoeia. An accompanying analysis in Neuron by researchers from the neuroscience unit of Pfizer praised the Roche study, but also pointed to the need for more work on how Trojan-horse therapeutics affect the basic physiology of moving through the brain’s Checkpoint Charlies. In fact, Roche subsidiary Genentech has had to continually refine its own version of a BBB transporter because the antibody had caused a drop in maturing red blood cells in animal studies.

Interest in this seemingly esoteric corner of pharmacology will persist.  Drug companies have already spent $1 billion on anti-amyloid antibodies. Getting over, around or through the Great Wall that is the BBB may be the only way to make these expenditures pay off. That means that research will no doubt continue apace on ways to build a better molecular Trojan Horse.

Source: Dan Budnik/Wikipedia Commons

Gary Stix About the Author: Gary Stix, a senior editor, commissions, writes, and edits features, news articles and Web blogs for SCIENTIFIC AMERICAN. His area of coverage is neuroscience. He also has frequently been the issue or section editor for special issues or reports on topics ranging from nanotechnology to obesity. He has worked for more than 20 years at SCIENTIFIC AMERICAN, following three years as a science journalist at IEEE Spectrum, the flagship publication for the Institute of Electrical and Electronics Engineers. He has an undergraduate degree in journalism from New York University. With his wife, Miriam Lacob, he wrote a general primer on technology called Who Gives a Gigabyte? Follow on Twitter @@gstix1.

The views expressed are those of the author and are not necessarily those of Scientific American.

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  1. 1. BCWestCoaster 5:59 pm 01/12/2014

    biOasis Technologies of Vancouver, BC is successfully shuttling therapeutic levels of drugs across the blood brain barrier in preclinical studies with a proprietary vector (Transcend). They have an internal program called ‘BT2111′ linking Transcend with trastuzumab (Herceptin) that has shown encouraging results so far. They also have current collaborations with four Pharmaceutical companies to see if Transcend can be used with their target compounds (Shire HGT, AbbVie, MedImmune, UCB Pharmaceuticals).

    Link to this
  2. 2. bsardi 10:45 pm 01/14/2014

    There is science showing the fat-soluble form of vitamin B1 (benfotiamine) eradicates both beta amyloid plaque and tau protein in the brain.

    Link to this

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