Study: Preclinical Mouse Model Shows Cognitive Improvement in Down Syndrome


Down syndrome, a disorder caused by the addition of a third chromosome 21, is marked by distinctive physical features and cognitive problems and delays. Partner Therapeutics, based in Lexington, Massachusetts, has teamed up with the University of Colorado to study mouse models of Down syndrome and compounds that might improve memory with age. 

Working with researchers at the University of Colorado Anschutz Medical Campus, researchers from Partner Therapeutics tested a well-known drug approved by the U.S. Food and Drug Administration called Leukine (sargramostim, glycosylated, yeast-derived rhuGM-CSF) in mice. The drug is known to improve cognition and brain pathology in a mouse model of Alzheimer’s disease.  

The research found an improvement in cognition in the mice model for Down syndrome that does not have Alzheimer’s disease pathology. Patients with Down syndrome are at higher risk of Alzheimer’s disease. The researchers published their findings in the journal Neurobiology of Disease

The study reads, “The population of people with DS continues to grow, and the average lifespan of people with DS continues to increase. There is, therefore, a critical need to develop therapeutics to improve cognitive function in people with DS and to help them to live more independently. In contrast to previous expectations that inhibiting inflammation and the innate immune system would be the most effective therapy for co-morbidities of DS, we report that treatment with GM-CSF, which has pro-inflammatory, anti-inflammatory and immune regulatory activities, which we have also confirmed in the Dp16 mice, reverses learning/memory deficits in a hippocampal-based task, ameliorates astrocyte abnormalities, and partially normalizes the numbers of interneurons that are reduced in 12-14-month-old male Dp16 mice, while also improving cognitive function in their WT [wild-type] littermates.” 

Sargramostim is a support medication for chemotherapy, used to stimulate the production, maturation and activation of three forms of white blood cells: neutrophils, macrophages and dendritic cells. It has been on the market for about 30 years. 

“Discovering a treatment that may help children and young adults with Down syndrome to develop their physical and mental capabilities is critical to improving their health and activities of daily living,” said senior author Huntington Potter, professor of neurology at the University of Colorado School of Medicine, director of the University of Colorado Alzheimer’s and Cognition Center and director of Alzheimer’s disease research at the Linda Crnic Institute for Down Syndrome. 

At this time, it is unknown if the drug, also known as GM-CSF, would have the same positive cognitive effects in humans. The CU Anschutz Medical Campus research group recently received a grant from the National Institutes of Health (NIH) and the National Institute on Aging to investigate the drug, whose brand name is Leukine, in young adults with Down syndrome. They will evaluate its safety, possible improvements in cognition, quality of life measures, and biomarkers tied to neuronal damage. 

The preclinical mice research found that one month of daily treatment with the drug reversed learning and memory losses, reversed the loss of specific nerve cells and significantly decreased the abnormal activation of the nerve-supporting astrocyte cells in the brains of the mice. In addition, a month of daily doses of the drug improved the cognitive function in normal aging mice. 

Potter recently published encouraging early clinical data from a Phase II trial of Leukine in patients with mild-to-moderate Alzheimer’s disease. The focus of that study was on whether modulating the innate immune system using GM-CSF/sargramostim could treat Alzheimer’s disease. The use of the drug did suggest improvements in some clinical symptoms and in some biomarkers associated with Alzheimer’s disease. 

“We are breaking new ground in studying sargramostim for multiple, different disorders — Down syndrome and Alzheimer’s disease,” Potter said. “We hope that this therapy, already proven to be safe for other diseases, has the potential to improve cognitive function in people with Down syndrome.” 

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