At tissue

February 28, 2019

Context counts.  If you are running towards the scene of a crime, you are doing something and you ARE something VERY different than if you are running away from the scene of a crime.  It's exactly the same thing: running, but the context makes the phenotype completely different.

So it is with a widely overlooked aspect of drugs and their targets: the tissues in which they act. A drug acting on the same target in the lung and the brain will result in very different effects naturally, with its action in the lung likely having something to do with respiration and its action in the brain likely having to do with cognition, motor or sensory phenomena, among other effects. (Unless, by enormous coincidence, it acts in the respiratory center of the brain.) Remarkably, we tend to file drugs away WITH their tissues and look no further. But, simply by looking at those other tissues, a new use for an already approved drug could be discovered. That’s called "repurposing" and it can be VERY lucrative for the biotech industry.

 

The latest example of this trend concerns the chemokine receptor CCR5.  Notorious for being one of the receptors targeted by HIV to infect, CCR5 is therefore often thought of solely as a blood/immune system thing. Indeed, there is already an FDA approved drug called maraviroc to treat HIV by inhibiting CCR5. But its tissue expression reveals that it is also expressed in neurons and the brain. That’s what makes this month’s study from UCLA interesting.

 

Researchers found that CCR5 inhibition prevents damage from stroke. The study is particularly convincing because of maraviroc: It showed that the drug induces recovery after stroke. Intriguingly, the highest level of medical evidence possible for their hypothesis was obtained without an actual Phase III trial: namely that humans with inherited absence of CCR5 have better outcomes after stroke. That could solve a long-standing mystery about those people, so-called "CCR5delta32 mutants": Why is their phenotype so silent if CCR5 is so important? Previously, it was theorized that perhaps the benefit of being resistant to HIV outweighed whatever CCR5 does immunologically, but that seemed weak as HIV is relatively recent in human evolution. Instead, the fact that it may provide a benefit for stroke and traumatic brain injury may be the crux of the matter. 

 

And since maraviroc has already been used extensively and safely in people with HIV and is validated as a CCR5-inhibitor in humans, its activity against stroke offers a compressed timeline to its being approved as a first-in-class drug to treat stroke victims. 

 

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