While neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and stroke affect millions of people worldwide, central nervous system (CNS) drug discovery remains a serious challenge. Issues of blood–brain barrier penetrance, first-pass metabolism, target affinity and selectivity, and translation from tissue culture to animal to human testing often represent immense hurdles for developing effective therapeutics. In 2014, $70 million was allocated to roughly 20 labs across the United States to develop “tissues/organs on a chip.” A group of researchers at Vanderbilt University has since worked to develop a brain on a chip—or, as it’s known there, the NVU (NeuroVascular Unit).
A brief intro to the NVU
The NVU uses a microfluidic system to supply cells with essential growth media across a membrane that separates the “brain” side (human stem cells that can be differentiated into neurons, astrocytes, or pericytes) from the “blood” side (human epithelial cells), in essence, recapitulating a human blood-brain barrier (BBB). Once the cells have appropriately matured, micropumps can deliver compounds to the NVU and, in turn, sample what’s released from the various sides of the unit in response to those drugs. Amazing, right?!
The amount of work that goes into developing such a device is astounding, and it’s only through multidisciplinary collaborations that such a project can even exist, let alone “produce.” The NVU is an essential intersection of cell culture, neuroscience, bioengineering, chemistry, pharmacology, stem cell research, translational medicine, and drug discovery. But what does this all mean? What can this thing do? And what might the future hold?
The BBB and Drug Discovery
Mechanisms of commonly used drugs: Toxicity predictions
An estimated 98% of compounds cannot readily cross the BBB, and of the ones that do, how they affect different cells within the brain is often unknown. The NVU is poised to allow scientists to step back and uncover the targets of commonly used drugs, and precise mechanisms by which they work. This is important for many reasons. As our population continues to live longer, it would be nice to know that the pill you’re taking every day is actually doing what we think it’s supposed to be doing in the cells it’s supposed to be targeting, and not doing so at the cost of other important neighboring cells, which could lead to even graver consequences over time.
Fast-tracking drug development
The NVU presents a means of studying what can and cannot cross the BBB. For instance, say we find that compound A moves readily across the BBB from “blood side” to “brain side,” while compound B does not. What’s the difference between A and B, and if we modify compound B to “look” more like compound A, can we get it across? While we know size is a major factor, this opens up other avenues for structural and chemical modifications to occur at much greater speed. Side note: This also means drugs that previously showed promise may come back into play with some modifications, or that drugs used to treat peripheral conditions may be repurposed for use in the CNS.
Imagine this all-too-common scenario: A drug has positive impact in preclinical rodent trials, only to fail in human trials. Now imagine this is solely due to species-specific BBB penetrance, which can be avoided using the NVU. Screening of compounds in a human model before actual human trials could fast-track (or kill) a large number of studies—but the brainpower, time, and money saved is immeasurable.
Looking toward the future
Suppose you could ”hook together” the human body’s major organs in a lab, treat “blood side” with a drug (that we now know can and does cross the BBB), and see the effects said drug has on the liver, kidney, heart, etc. Or reverse that and flip it—treat the heart, and see if there are changes in the brain. The potential of these system-wide study types is astronomical, and it’s in the works.
As I mentioned earlier, there are many labs developing “organ on a chip” models with support from the NIH—including brain, heart, muscle, lung, liver, kidney, gastrointestinal systems, reproductive tracts, blood vessels, adipose, and skin—all with the hope of providing crucial information that will allow us to develop new and more effective treatments for—well, you name it!
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