In her lab at Brigham and Women’s Hospital in Boston, Choi-Fong Cho is growing tiny, balled-up versions of the blood-brain barrier, one of neuroscience’s most notorious opponents.
The barrier lines blood vessels in the brain to block foreign invaders, but it also stops most drugs from getting into the central nervous system. It’s foiled countless treatments that looked promising in animals, only to never make it into the brains of patients.
Cho wants to make the process of scouring for drugs that can cross the barrier far less difficult. So the neuroscientist developed her organoids — tiny bunches of brain cells — to help determine which chemicals can get into the brain.
“We want to change the way people to look at drug development in neuroscience,” Cho said.
Drug companies have poured billions into experimental treatments for Alzheimer’s disease, glioblastoma, and other neurological conditions with the hope that they can beat the blood-brain barrier.
Roche developed a “brain shuttle” to transport therapeutic molecules past the blood-brain barrier. At Biogen, scientists are searching for a way to hijack the transporter proteins that carry certain nutrients across the barrier, tricking them into carrying therapeutic cargo into the brain.
And at Impel NeuroPharma, researchers are working on a platform to bypass the blood-brain barrier by spraying drugs deep into the nose.
But often, such treatments have come up short in patients.
Experts are hopeful that models like Cho’s will give researchers a better idea of whether the drug candidates they’re studying stand a chance against the blood-brain barrier — and speed up the process of finding compounds that can make it across.
“We can now screen things in a much more rapid fashion to see whether something can get across,” said Dr. Antonio Chiocca, the chief neurosurgeon at Brigham and Women’s Hospital and a brain cancer researcher who collaborates with Cho.
Grow your own blood-brain barriers
To grow her own blood-brain barriers, Cho started with the basics. She took the three main cellular components of the barriers — human endothelial cells, pericytes, and astrocytes — and cultured them together in the lab. When she did, they started forming little balls of cells, or spheroids. The endothelial cells and pericytes wrapped themselves around an astrocyte core.
Then she added small molecule drugs into the environment and waited. The mini-barriers kept most compounds from getting into the center, or the “brain,” of the spheroids. If a significant amount of the substance made it inside, Cho and her colleagues presumed it might also be able to cross the blood-brain barrier.
“We can look to see how much of a drug has actually trespassed the surface and accumulated within the core,” Cho said.
Cho uses one of two techniques to figure out whether a molecule snuck into the spheroid’s center. For some, she uses fluorescent labels that allow her to determine, with the help of a microscope, whether they’ve made it.
“We want to change the way people to look at drug development in neuroscience.”
Choi-Fong Cho, Brigham and Women's Hospital
For those that can’t be lit up under a microscope, she uses mass spectrometry to pinpoint where the molecules landed. Cho and her colleagues are now working to find better ways to track what happens to the molecules once they approach the blood-brain barrier.
The spheroids aren’t without limitations. As with any model, there’s a question of accuracy: Will what happens in a mini-barrier translate to an animal model, and will that animal model translate to real patients?
“In vitro models are no substitute for in vivo models,” said Dr. Edward Neuwelt, a neurosurgeon who runs a blood-brain barrier research program at Oregon Health and Science University. Anything that appears to cross the blood-brain barrier in the spheroids would still need to be validated with animal testing.
But experts agree that better in vitro models would make it easier to figure out which compounds are worth trying in an animal model, sparing precious time and money for research.
“This model really is to help us narrow down from many, many hits to a few specific ones to be tested in vivo,” Cho said.
So far, Cho and her colleagues have used small molecules in the model. They’re now trying to see whether the models can be used to study how other substances, like bacteria, interact with the blood-brain barrier.
A simple blueprint for a new idea
Cho and her colleagues published a paper about the spheroids in Nature Communications last year and have been presenting to other researchers on their work. The idea has quickly sparked interest among drug makers and other academic researchers.
“A lot of people have been expressing their interest in working with the model or working with us to test their molecules of interest,” Cho said.
Chiocca, whose lab is focused on creating new genetic therapies for malignant brain tumors, is now using Cho’s models in his own research. He’s trying to figure out whether it’s possible to transfer genetic material and certain compounds that can target brain tumors across the blood-brain barrier. The models have made that work easier.
“Animal models are expensive,” Chiocca explained. “Using these organoids is much easier to screen rapidly and screen a lot more potential treatments.”