For the first time, scientists have reversed memory and learning deficits in mice following traumatic brain injuries. This new research could someday lead to treatments for head trauma and debilitating cognitive diseases.
In a study published Monday in The Proceedings of the National Academy of Sciences, scientists at the University of California in San Francisco found that a new experimental drug can restore normal function in mice following two types of TBIs.
Geoffrey Manley, the chief of neurosurgery at Zuckerberg San Francisco General Hospital, sometimes sees dozens of TBI cases a week. He was not involved in the study but called the results “very exciting” from a clinical perspective.
In previous trials where drugs proved effective in mice, treatments were administered right after the injury, according to Manley. But diagnosis and treatment within a few hours does not always occur with humans, he explained. The new successful treatment, which was administered to the mice two to four weeks after their injury, is “more clinically tractable,” he said.
The UCSF researchers actually weren't pursuing a brain injury treatment when they discovered the new drug. Scientists in principal investigator Peter Walter’s lab screened 100,000 chemicals, looking for one that would inhibit a stress response in yeast. This same response allows cancer cells to grow and divide despite many mutations, and chronic activation has been linked to brain inflammation, which is a feature of TBI, as well as diseases like Alzheimer’s and Parkinson's.
When the scientists found that a chemical called ISRIB (“iz-rib”) could inhibit the cellular response, Walter was so inspired he sculpted it. The next step was to find a disease model for testing it. That’s where Regis Kelly came in.
Kelly is the director of QB3, a think tank connecting Bay Area researchers in the University of California system with industry partners. He is also a neuroscientist married to a woman with early-onset Alzheimer’s. His institute's mission is to get ideas out of academic labs and into the market — ideas like a new drug for TBIs.
Kelly was Walter’s mentor when he came to UCSF over 30 years ago. About the time Walter became interested in testing the capacity for ISRIB to work as a drug, Kelly stumbled on a paper from the lab of UCSF neuroscientist Susanna Rosi describing a mouse model for traumatic brain injury. Kelly played matchmaker, bringing the two together and helping them secure a grant to examine the effect of ISRIB on traumatic brain injury.
Scientists in Walter's and Rosi's labs tested the drug on two different mouse models. One mimicked focal injuries, which occur at a specific spot in the brain when someone has a stroke or is hit by a golf ball, for example. The other model was for concussive injuries like those suffered from a very hard fall or in whiplash during a car accident.
In the first model, one month following a surgical focal injury, the mice were shown how to navigate a water maze. Several days later, those that had received treatment during the training could find their way through the maze faster than those that had not gotten any treatment. The difference persisted even a month after the treatment stopped.
In the second test, two weeks after a concussive injury, mice had to find the escape tunnel among 40 holes in a table in a room of bright lights and noise. The animals that received ISRIB at this point had an easier time finding the tunnel. By the third and final day of tests, the treated mice were finding the tunnel just as quickly as uninjured mice.
Mouse brains are different from human brains, but Cesario Borlongan, distinguished professor of neurosurgery at the University of Southern Florida, noted three reasons ISRIB might be more likely to be effective than previous trials for people. Because it is a small molecule and can cross the blood-brain barrier, the drug would likely not have to be injected directly into the brain. And the fact that treatment with ISRIB is still effective weeks after injury gives it an advantage over drugs that were used in mouse models immediately following the trauma, Borlongan said. Most importantly, ISRIB worked in two different types of brain injury.
The research “provides hope, not only for us but for our patients, that we will have something that could be used to treat them,” Manley said. Kelly agreed, saying, “This work Peter and Susanna do gives great hope to Alzheimer’s caretakers like me.”
ISRIB has been licensed by Calico, a biotechnology company founded by Google. Scientists at Calico and in the two UCSF labs are working to identify the specific mechanisms of ISRIB's action to determine whether it might act similarly in humans.
After that, Borlongan said, the next step will be testing whether the drug is safe for humans.