A paradigm-shifting study from the Centre for Addiction and Mental Health (CAMH) shows an experimental drug, GL-II-73, has the potential to restore memory and cognitive function in a mouse model of Alzheimer's disease. Recently published in Neurobiology of Aging , the study demonstrates that the drug improves memory deficits and reverses brain cell damage, offering hope for improving cognitive functioning, delaying Alzheimer's progression, and potentially preventing some of the brain damages associated with the disease.
Alzheimer's disease is the most common form of dementia, and nearly 50 million people worldwide are affected by Alzheimer's or related dementia. It is a progressive neurological condition that leads to memory loss, cognitive decline, and changes in behaviours, significantly impacting the lives of patients and their families.
This paper builds on 12 years of previous research led by Dr. Etienne Sibille, Scientific Director of the Neurobiology of Depression and Aging Program at CAMH, and Dr. Thomas Prevot, Scientist in the same program, who are the co-lead authors of the study. "We have uncovered a critical vulnerability in brain pathways impacted by Alzheimer's and other cognitive disorders, and this drug holds promise as a novel treatment," said Dr. Sibille. "By restoring neural function and reversing memory deficits, GL-II-73 represents a potential early intervention for Alzheimer's, addressing the root cause of memory loss—something no current drugs can achieve."
The study tested the drug in a mouse model of Alzheimer's disease, using both young and older mice to represent the early and later disease stages. Two groups were included: normal mice and genetically engineered mice prone to developing beta-amyloid buildup, a hallmark of Alzheimer's. Genetically engineered mice received either a single dose of GL-II-73 before testing or underwent chronic treatment for four weeks. Researchers then assessed memory performance in all groups.
Results showed GL-II-73 significantly improved memory in younger and older mice with Alzheimer's symptoms. In early-stage disease models, a single dose of the drug reversed memory deficits, enabling treated mice to perform as well as healthy controls. Chronic treatment was still beneficial for mice at later stages of the disease, though less effective, indicating that GL-II-73 can partially improve memory impairments even after significant cognitive decline.
The findings suggest that the drug could have significant implications for Alzheimer's disease, where there are no current treatments that can fully slow or reverse cognitive decline. Unlike many existing drugs that target beta-amyloid buildup, GL-II-73 selectively targets GABA receptors in the hippocampus to restore brain function and repair damaged neural connections. Early studies also suggest the drug shows promise for other mental health conditions associated with cognitive impairment, including depression, epilepsy, and schizophrenia.
"GL-II-73 demonstrated an incredible ability to restore cognitive function in a mouse model of Alzheimer's, particularly when administered early in the disease," added Dr. Prevot. "In addition to improving memory, the drug helped grow and strengthen neural connections in the brain, which are essential for maintaining learning and memory. This could be a critical step forward for treating Alzheimer's and other cognitive disorders."
In 2019, CAMH supported Dr. Sibille and his team in establishing Damona Pharmaceuticals , a spinoff company to help commercialize this research. This process was facilitated by CAMH's Industry Partnerships and Technology Transfer Office. "Damona was established to focus on developing treatments that reverse cognitive deficits and improve life for patients living with Alzheimer's disease, depression, schizophrenia, and other brain disorders," said John Reilly, CEO of Damona Pharmaceuticals. "With seed-stage financing from top venture capital firms, we have built an exceptional management team and advanced development of this lead molecule, which recently received U.S. Food and Drug Administration (FDA) clearance for human clinical trials. We look forward to enrolling patients in a Phase 1 clinical trial in the first half of 2025."
Funding for the study was provided by the Weston Brain Institute.
