Natural Drug Approved for White Blood Cell Recovery Can Be Repurposed To Improve Cognition in Alzheimer’s Patients

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A Phase II clinical trial shows the innate immune system is a viable target for therapeutic intervention in Alzheimer’s disease.

The clinical trial data reported in the article “Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer’s disease” published in the journal Alzheimer’s & Dementia: Translational Research & Clinical Interventions, by scientists from the University of Colorado Alzheimer’s and Cognition Center at the University of Colorado Anschutz Medical Campus (CU Anschutz), shows a man-made version (Sargramostim) of a natural protein (granulocyte-macrophage colony stimulating factor, GM-CSF) may have both disease-modifying and cognition-enhancing activities in Alzheimer’s disease patients.

“The goal of the clinical trial was to examine the impact of a natural human protein called granulocyte-macrophage colony stimulating factor (GM-CSF) on people living with Alzheimer’s disease. We tested GM-CSF because people with rheumatoid arthritis tend not to get Alzheimer’s disease and we had previously found this protein, which is increased in the blood of people with rheumatoid arthritis, reduced amyloid deposition in Alzheimer’s mice and returned their poor memory to normal after a few weeks of treatment. Thus, naturally increased levels of GM-CSF in people with rheumatoid arthritis may be one reason that they are protected from Alzheimer’s disease,” says Huntington Potter, PhD, director of the CU Alzheimer’s and Cognition Center, who together with Jonathan Woodcock, MD, Timothy Boyd, PhD, and collaborators carried out the new trial.

Patients with Alzheimer’s disease exhibit markers of inflammation in their brains, cerebrospinal fluid and serum. Targeting inflammation using non-steroidal anti-inflammatory drugs however, have not yielded any beneficial responses in patients with Alzheimer’s disease or mild cognitive impairment (MCI) in earlier trials.

Sargramostim/GM-CSF is prescribed to boost white blood cells after cancer treatments or exposure to radiation. The protein stimulates the bone marrow to make more macrophages and granulocytes, specific types of white blood cells, and progenitor cells that repair blood vessels. These white blood cells circulate throughout the body and remove cells, bacteria and amyloid deposits and also repairing blood vessels.

The current data reveals Sargramostim/GM-CSF is also effective in treating and improving memory in people with mild-to-moderate Alzheimer’s disease.

“Human GM-CSF is the active compound in the known human drug Sargramostim, and we are the first to study its effect on people with Alzheimer’s disease,” says Potter.

The team carried out a randomized, double-blind, placebo-controlled Phase II trial (NCT01409915) to test the safety and efficacy of Sargramostim treatment in participants with mild-moderate Alzheimer’s disease.

Study participants were either administered Sargramostim at the standard FDA dose of 250 μg/m2/day by subcutaneous injection, or saline for five days a week for three weeks. The study included 20 participants in the test and placebo group. Most participants in the study were recruited and treated at CU Anschutz with a few from the University of South Florida. The CU Anschutz researchers then conducted and studied multiple neurological, neuropsychological, cell, cytokine, Alzheimer’s pathology biomarkers and neuroimaging assessments.

The investigators found that short-term Sargramostim treatment increased innate and other immune cells, modulated cytokine measures, and was safe and well-tolerated by participants. They also found cognition memory improved by almost two points in the 30 point Mini-Mental State Exam. Brain amyloid, tangles, neurodegeneration, and measures of blood biomarkers of Alzheimer’s disease, all improved toward normal.

“These results suggest that short-term Sargramostim treatment leads to innate immune system activation, cognition and memory improvement, and partial normalization of blood measures of amyloid and tau pathology and neuronal damage in participants with mild-to-moderate Alzheimer’s disease,” says Potter. “This surprising finding that stimulating the innate immune system and modulating inflammation may be a new treatment approach and induced us to start a larger trial of Sargramostim in Alzheimer’s disease with more participants treated over a longer time.”

The larger trial will be funded by the Alzheimer’s Association/Part The Cloud, the University of Colorado, the Global Down Syndrome Foundation, and by a large grant recently awarded from the National Institute on Aging.

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