Promise of ISR Inhibitors In Treating Age-Related Cognitive Decline

January 27, 2021

By Deborah Borfitz

January 27, 2021 | An intracellular signaling network known as the integrated stress response (ISR) is of growing interest to drug developers because it seems to be affecting so many clinical conditions, ranging from Down syndrome and traumatic brain injury (TBI) to hearing loss, some types of prostate cancer, and the natural process of aging, according to Susanna Rosi, Ph.D., director of neurocognitive research in the UCSF Brain and Spinal Injury Center. 

The original study in PNAS (DOI: 10.1073/pnas.1707661114) showing that ISR inhibition reverses cognitive deficits after TBI was conducted in the Rosi lab at the University of California, San Francisco, where she is a professor in the departments of neurological surgery and physical therapy and rehabilitation science. The “next logical step” was to see if the same approach could undo age-related cognitive decline, which indeed it could and in a matter of days—at least in mice. 

As described in a study published late last year in eLife (DOI: 10.7554/eLife.62048), an ISR inhibitor reversed spatial memory deficits and improved working memory in old mice. It also reset the function of their immune system's T cells, making it a potential intervention for combating age-related cognitive decline in otherwise healthy individuals. 

After being treated with an ISR inhibitor, demented mice were able to find a hidden platform in a watery maze just as well as their younger, normal counterparts and their mental flexibility endured for weeks, says Rosi. Previous studies have focused on prevention and early treatment of cognitive deficits, based on the assumption that any damage done would be permanent.

After the mice were given a few treatments with the drug, common signatures of neuronal aging in their hippocampal cells disappeared, Rosi says. The electrical activity of neurons became sprightlier and more responsive to stimulation, and cells showed more robust connectivity with cells around them and the connections were as stable as that seen in younger mice. 

On the investigative team in both cases was her UCSF colleague Peter Walter, Ph.D., Howard Hughes Medical Institute investigator and professor in the department of biochemistry and biophysics, whose lab discovered the experimental drug ISRIB (ISR InhiBitor) used in the studies in 2013. The small-molecule inhibitor was licensed to Calico in 2015. 

Much of the preclinical drug development is being done at Google-backed Calico (UCSF licensed), which has partnered with AbbVie on ISRIB. Others, including GlaxoSmithKline and Denali Therapeutics, are also actively investigating compounds working on the same pathway.

If ISRIB is applicable in humans, the implications are enormous, says Rosi. Among individuals with TBI alone, 16 million people in the U.S. are suffering long-term, trauma-induced cognitive impairment.


Cellular Reboot 

ISR activation “puts the brakes on the cell’s protein-synthesis machinery,” explains Rosi, and acts as a “failsafe mechanism critical to weeding out any misbehaving cells.” But if ISR gets stuck in the “on” position in a tissue like the brain, serious problems ensue as cells lose the ability to perform their usual functions. 

Normally, ISR gets activated in the brain when it detects problems such as infection, a cancer-promoting gene mutation, physical trauma, or protein aggregation, Rosi says. 

But if ISR goes into overdrive, cognitive resources get physiologically “trapped” in a vicious cycle of cellular stress, she continues. As suggested by ISRIB’s rapid effects, this blockage contributes significantly to age-related cognitive losses but is reversible. “The brain is not fully compromised, as otherwise we were thinking.” 

ISRIB “resets” cellular protein production, restoring memory function after TBI that lasts up to six months in mice—the equivalent of 18 to 24 years in humans, says Rosi. In the eLife study on old mice, the research team was only able to demonstrate that the changes persisted for three weeks due to the rodent’s short lifespan. How long the cognitive benefits may last remains one of the outstanding research questions.


Human Trials In The Offing

A review co-authored by Walter and published last year in Science (DOI: 10.1126/science.aat5314) provides an overview of diseases of the brain associated with ISR activation. In addition to TBI and age-related cognitive decline, the list included frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, Down syndrome (characterized by a high incidence of Alzheimer’s), Charcot-Marie-Tooth disease (a group of inherited disorders causing nerve damage), vanishing white matter disease (genetic disorder where the body doesn’t make enough myelin), and prion disease (involving abnormally folded proteins).

Recent evidence has shown that the ISR serves as a “universal regulator” of long-term memory formation, they write. Inhibiting the ISR enhances this process, while activation of the IRS prevents it.

The role of the proteins altered by ISR activation remains unclear, and ISR gene expression signatures and functional consequences will need to be mapped, they add. Linking mechanistic discoveries to clinical applications, they further suggest, may require the use of convergent models, including organoids. 

Since ISRIB has proven to be completely non-toxic in mice when working with a ISRIB derivative for TBI applications, Rosi says she and Walters are “really motivated to… push it to humans as soon as possible. Every day, I get at least five to 10 emails from people suffering asking if they can be in any clinical trials.” 

No clinical trials specific to reversing cognitive defects via the ISR pathway have started, says Rosi. But they will need to happen in tandem with basic research to understand, in a cell-specific manner, where ISRIB is operating. “Is it specifically working on immune cells and the changes seen in the brain are a secondary response, or is it working in parallel on immune cells and the brain?” 

Similarly, she adds, it needs to be determined if the impact of cellular stress on protein production is common across certain kinds of cells, such as those involved in neurological diseases, or if all cells respond the same way.