ISRIB

Human trials?

Drug Reverses Memory Failure Caused by Traumatic Brain Injury https://www.ucsf.edu/news/2017/07/407656/drug-reverses-memory-failure-caused-traumatic-brain-injury

In an unprecedented finding, UC San Francisco scientists used an experimental drug to completely reverse severe learning and memory impairments caused by traumatic brain injury (TBI) in mice. Surprisingly, the drug fully restored the ability to learn and remember in the brain-injured mice even when the animals were first treated as much as a month after injury.

The latter results are particularly striking, as most research on brain injury and stroke has suggested that treatments must be initiated as quickly as possible to preserve normal function.

The researchers said the new study offers a promising new avenue for the treatment of TBI in humans, which affects nearly two million individuals annually in the U.S. – one every 21 seconds. In addition to causing serious cognitive deficits, which can be short-lived or permanent, TBI is also a leading risk factor for the development of Alzheimer’s disease and other forms of dementia. But dozens of seemingly promising treatments have failed in clinical trials, and no approved therapies are currently available.

Two Types of Brain Injuries

The drug used in the new research, known as ISRIB (pronounced “iz-rib”), was discovered in 2013 in the laboratory of Peter Walter, PhD, professor of biochemistry and biophysics at UCSF and co-senior author of the new study, which will be published online during the week of July 10, 2017, in Proceedings of the National Academy of Sciences. ISRIB was licensed in 2015 to Calico, a company involved in understanding the biology that controls the human lifespan.

“This is extraordinarily exciting,” said Walter, also a Howard Hughes Medical Institute (HHMI) investigator. “We think that ISRIB may uncover an untapped reservoir in the brain that allows damaged memory circuits to be repaired.”

In the new research, scientists in the laboratory of co-senior author Susanna Rosi, PhD, professor of physical therapy and rehabilitation sciences and of neurological surgery at UCSF, tested whether ISRIB – which had previously been shown by Walter and colleagues to enhance memory in normal mice – could improve the ability to learn and form memories in mice with two different types of brain injury, each of which are known to degrade learning and memory in humans.

“In general, animals with these injuries never learn well again,” said Rosi, a member of the UCSF Weill Institute for Neurosciences and director of neurocognitive research at UCSF’s Brain and Spinal Injury Center, located at partner institution Zuckerberg San Francisco General Hospital. “So it’s remarkable that ISRIB could restore the ability to form new memories even when we delayed giving the drug for four weeks after the injury. This has not been considered possible.”

Localized brain injuries called focal contusions can affect spatial memory, which helps both mice and humans navigate through the world and complete necessary everyday tasks. Concussive brain injuries – which cause diffuse trauma to the whole brain – can degrade “working memory,” a temporary storage system that is critical for reasoning and decision-making.

Restoration of Ability to Learn Persisted

To test ISRIB’s potential effects after focal injury, both normal and brain-injured mice were placed in a “radial-arm water maze,” in which they had to learn the location of a platform hidden under milky water in one of eight arms of the maze.

Mice are averse to swimming, and after a brief training period normal mice improve steadily on this task, eventually finding the platform quite quickly after being placed into the maze. But brain-injured mice continue to make errors – swimming into incorrect arms of the maze in search of the platform – with no sign of improvement, long after training.

In the new research, however, when brain-injured mice were given three injections of ISRIB beginning four weeks after injury (the injections were spaced one day apart), their performance in the maze was indistinguishable from that of normal mice, and the restoration of their ability to learn persisted for a week after the last injection.

Given ISRIB’s pharmacology, Rosi said, the persistence of its effects is intriguing, and indicates that it may induce some durable change in the brain. “ISRIB’s half-life is less than a day, and when the mice demonstrated intact memory ability a week after receiving it, we know there is only the most miniscule trace of the drug left in their bodies.”

To test whether ISRIB could restore working memory after concussive brain injury, members of Rosi’s lab used a modified Barnes maze, which resembles a tabletop perforated with 40 holes; one of these holes leads to an escape tunnel, which normal mice efficiently learn to locate.

As with the radial-arm water maze, brain-injured mice usually perform poorly on this test, but when the mice with concussive injuries received ISRIB injections – in this case, four daily injections, beginning two weeks after injury – they again performed as well as their normal counterparts.

Blocks Part of the Integrated Stress Response

ISRIB works by blocking a part of a protective cellular system known as the Integrated Stress Response, or ISR (the drug’s name means “Integrated Stress Response InhiBitor”). When cells are injured or under stress from infection or a lack of nutrients, the ISR slows down translation, the process by which the genetic instructions encoded within DNA are converted into functional proteins. By binding to a central cellular player involved in translation, ISRIB allows stressed cells to override the ISR, with protein translation proceeding apace.

the ISRIB molecule

The ISRIB drug was discovered in 2013 in the laboratory of Peter Walter, PhD.

In addition to the memory experiments described in the new paper, Walter and Rosi report experiments with brain slices showing that both focal and concussive injury activate the ISR in the hippocampus, a brain region that is crucial for memory, and that the ISR remains active for 28 days after the injury. Applying ISRIB to the slices not only dampened the effects of the ISR, but restored a process known as long-term potentiation, or LTP, a persistent strengthening of neural connections that is believed to be crucial to the formation of new memories.

Walter, who has won both the Albert Lasker Basic Medical Research Award and the Shaw Prize, two of the most prestigious prizes in biomedicine, for groundbreaking work on a system closely related to the ISR, believes that ISRIB may reverse memory loss in damaged nerve cells by restoring proper control of the synthesis of proteins that are essential to LTP and other cellular bases of memory. But he and Rosi “are still in a discovery phase” in understanding ISRIB’s mechanism of action, Walter said. “We are exploring. We are going into the unknown.”

And as startling as the new results are, Rosi said, the drug’s effectiveness must undergo many more studies before it would be a candidate for clinical trials to treat brain-injured patients, work that she and Walter are undertaking with an Innovation Award from the UCSF Weill Institute for Neurosciences, which they shared in October 2016 for their work on ISRIB and TBI.

“We need to do much more research,” Rosi said, “but I have high hopes that this drug can bring back lost memory capacity to our patients who have suffered brain injuries.”

*

Drug Reverses Age-Related Mental Decline Within Days https://www.ucsf.edu/news/2020/12/419201/drug-reverses-age-related-mental-decline-within-days

Rapid Rejuvenation of Mental Faculties in Aged Mice Implicates Reversible Physiological ‘Blockage’ Behind Age-Related Cognitive Losses

Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists. The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.

In the new study, published Dec. 1, 2020, in the open-access journal eLife, researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function.

“ISRIB’s extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological “blockage” rather than more permanent degradation,” said Susanna Rosi, PhD, Lewis and Ruth Cozen Chair II and professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science.

“The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress,” added Peter Walter, PhD, a professor in the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”

Could Rebooting Cellular Protein Production Hold the Key to Aging and Other Diseases?

Walter has won numerous scientific awards, including the Breakthrough, Lasker and Shaw prizes, for his decades-long studies of cellular stress responses. ISRIB, discovered in 2013 in Walter’s lab, works by rebooting cells' protein production machinery after it gets throttled by one of these stress responses – a cellular quality control mechanism called the integrated stress response (ISR; ISRIB stands for ISR InhiBitor).

The ISR normally detects problems with protein production in a cell — a potential sign of viral infection or cancer-promoting gene mutations — and responds by putting the brakes on cell’s protein-synthesis machinery. This safety mechanism is critical for weeding out misbehaving cells, but if stuck in the on position in a tissue like the brain, it can lead to serious problems, as cells lose the ability to perform their normal activities, Walter and colleagues have found.

In particular, recent animal studies by Walter and Rosi, made possible by early philanthropic support from The Rogers Family Foundation, have implicated chronic ISR activation in the persistent cognitive and behavioral deficits seen in patients after TBI, by showing that, in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.

The cognitive deficits in TBI patients are often likened to premature aging, which led Rosi and Walter to wonder if the ISR could also underlie purely age-related cognitive decline. Aging is well known to compromise cellular protein production across the body, as life’s many insults pile up and stressors like chronic inflammation wear away at cells, potentially leading to widespread activation of the ISR.

“We’ve seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline,” said Rosi, who is director of neurocognitive research in the UCSF Brain and Spinal Injury Center and a member of the UCSF Weill Institute for Neurosciences. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step.”

Improves Cognition, Boosts Neuron and Immune Cell Function

In the new study, researchers led by Rosi lab postdoc Karen Krukowski, PhD, trained aged animals to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice, much better than animals of the same age who didn’t receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily – a test of mental flexibility for aged mice who, like humans, tend to get increasingly stuck in their ways. The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.

To understand how ISRIB might be improving brain function, the researchers studied the activity and anatomy of cells in the hippocampus, a brain region with a key role in learning and memory, just one day after giving animals a single dose of ISRIB. They found that common signatures of neuronal aging disappeared literally overnight: neurons' electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another usually only seen in younger mice.

The researchers are continuing to study exactly how the ISR disrupts cognition in aging and other conditions and to understand how long ISRIB’s cognitive benefits may last. Among other puzzles raised by the new findings is the discovery that ISRIB also alters the function of the immune system’s T cells, which also are prone to age-related dysfunction. The findings suggest another path by which the drug could be improving cognition in aged animals, and could have implications for diseases from Alzheimer’s to diabetes that have been linked to heightened inflammation caused by an aging immune system.

“This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus,” said Rosi. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.”

Broad Effects Exemplify ‘Serendipity’ of Basic Research

Rosi and Walter were introduced by neuroscientist Regis Kelly, PhD, executive director of the University of California’s QB3 biotech innovation hub, following Walter’s 2013 study showing that the drug seemed to instantly enhance cognitive abilities in healthy mice. To Rosi, the results from that study implied some walled-off cognitive potential in the brain that the molecule was somehow unlocking, and she wondered if this extra cognitive boost might benefit patients with neurological damage from traumatic brain injury.

The labs joined forces to study the question in mice, and were astounded by what they found. ISRIB didn’t just make up for some of the cognitive deficits in mice with traumatic brain injury – it erased them. “This had never been seen before,” Rosi said. “The mantra in the field was that brain damage is permanent – irreversible. How could a single treatment with a small molecule make them disappear overnight?”

Further studies demonstrated that neurons throughout the brains of animals with traumatic brain injury are thoroughly jammed up by the ISR. Using ISRIB to release those brakes lets brain cells immediately get back to their normal business. More recently, studies in animals with very mild repetitive brain injury – akin to pro athletes who experience many mild concussions over many years – showed that ISRIB could reverse increased risk-taking behavior associated with damage to self-control circuits in the frontal cortex.

“Added to this, Karen’s new results in aging mice are just amazing. It’s not often that you find a drug candidate that shows so much potential and promise,” Walter added. “This project also shows the power of the UCSF community – Susanna and I didn’t know each other and were living in different worlds until Regis Kelly brought us together, making this powerful connection that neither of us had realized before.”

“Amazing breakthroughs like this need more than the brilliance and experimental skills of Susanna and Peter,” said Kelly. “They also need donors like the Rogers Family Foundation willing to bridge the gap between great basic research and products that could be highly beneficial to society.”

ISRIB has been licensed by Calico, a South San Francisco, Calif. company exploring the biology of aging, and the idea of targeting the ISR to treat disease has been picked up by many other pharmaceutical companies, Walter says.

One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors, Walter says. First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state, after which it can still respond normally to problems in individual cells. Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form – against an aggressive viral infection, for example.

Naturally, both of these factors make the molecule much less likely to have negative side effects – and more attractive as a potential therapeutic. “It almost seems too good to be true, but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window,” Walter said.

*

Memory-enhancing drug reverses effects of traumatic brain injury in mice https://www.sciencemag.org/news/2017/07/memory-enhancing-drug-reverses-effects-traumatic-brain-injury-mice

Whether caused by a car accident that slams your head into the dashboard or repeated blows to your cranium from high-contact sports, traumatic brain injury can be permanent. There are no drugs to reverse the cognitive decline and memory loss, and any surgical interventions must be carried out within hours to be effective, according to the current medical wisdom. But a compound previously used to enhance memory in mice may offer hope: Rodents who took it up to a month after a concussion had memory capabilities similar to those that had never been injured.

The study “offers a glimmer of hope for our traumatic brain injury patients,” says Cesario Borlongan, a neuroscientist who studies brain aging and repair at the University of South Florida in Tampa. Borlongan, who reviewed the new paper, notes that its findings are especially important in the clinic, where most rehabilitation focuses on improving motor—not cognitive—function.

Traumatic brain injuries, which cause cell death and inflammation in the brain, affect 2 million Americans each year. But the condition is difficult to study, in part because every fall, concussion, or blow to the head is different. Some result in bleeding and swelling, which must be treated immediately by drilling into the skull to relieve pressure. But under the microscope, even less severe cases appear to trigger an “integrated stress response,” which throws protein synthesis in neurons out of whack and may make long-term memory formation difficult.

In 2013, the lab of Peter Walter, a biochemist at the University of California, San Francisco (UCSF), discovered a compound—called ISRIB—that blocked the stress response in human cells in a dish. Surprisingly, when tested in healthy mice, ISRIB boosted their memory. Wondering whether the drug could also reverse memory impairment, Walter teamed up with UCSF neuroscientist Susanna Rosi to study mouse models of traumatic brain injury. First, they showed that the stress response remains active in the hippocampus, a brain region important for learning and memory, for at least 28 days in injured mice. And they wondered whether administering ISRIB would help.

Rosi and her team first used mechanical pistons to hit anesthetized mice in precise parts of their surgically exposed brains, resulting in contusive injuries, focused blows that can also result from car accidents or being hit with a heavy object. After 4 weeks of rest, Rosi trained the mice to swim through a water maze, where they used cues to remember the location of a hidden resting platform. Healthy mice got better with practice, but the injured ones didn’t improve. However, when the injured mice were given ISRIB 3 days in a row, they were able to solve the maze just as quickly as healthy mice up to a week later, the researchers report today in the Proceedings of the National Academy of Sciences.

“We kept replicating experiments, thinking maybe something went wrong,” Rosi says. So the team decided to study ISRIB in a second model of traumatic brain injury known as a closed head injury, which resembles a concussion from a fall. They again used a mechanical piston, but this time landed a broad blow to the back of the skull. Two weeks later, the mice were trained on a tougher maze, full of bright lights and loud noise. They had to scurry around a tabletop with 40 holes, looking for the one with an escape hatch. Again, while the uninjured mice improved at the task, the concussed mice never got the hang of it. But after four daily doses of ISRIB, the concussed mice performed as well as their healthy counterparts. “This is the most exciting piece of work I’ve ever done, no doubt,” Rosi says.

“Paradigm shift is not too strong a term to use,” says Ramon Diaz-Arrastia, neurologist and director of clinical traumatic brain injury research at the University of Pennsylvania. “This … shows for the first time that a therapy in the chronic period of traumatic brain injury can have pretty potent effects.” Walter agrees. “Normally you would give up on these mice and say nothing can be done here,” he says. “But ISRIB just magically brings the cognitive ability back.”

Still, Borlongan cautions that studies in animals often don’t pan out when tested in humans. He says that this drug has a leg up, though, because it was tested in two models and also readily crosses the blood-brain barrier, which prevents many drugs that look good on paper from entering the brain and having an effect.

If the therapy translates to humans, it could be a boon for soldiers returning from war, who sometimes wait weeks between leaving the battlefield and arriving home for treatment. Brian Head, a neurobiologist at the VA San Diego Healthcare System in California notes that traumatic brain injury is still hard to diagnose, especially with veterans that show up to the clinic long after the injury. “But right now nothing else is working, and giving a compound [that works] a month later is really impressive.”

In 2015, ISRIB was licensed to the secretive Google spinout company Calico, which studies the biology of aging and life span. Walter says his lab has a research agreement with Calico to pursue “basic mechanistic work” on ISRIB, but that the new study was not funded by Calico. Google declined to comment on the new research.

Although the protein target of ISRIB is known, the exact manner in which the drug restores memory is hazy. The team hypothesizes that ISRIB may work by allowing normal protein synthesis—essential for making new neuronal connections and thus forming new memories—to resume, which would otherwise be blunted by the integrated stress response. “Even if this drug doesn’t materialize, other ways of manipulating the integrated stress response may lead to an effective treatment in the future,” Walter says.