Alzheimer?s disease (AD) treatments designed to target the amyloid-beta peptide have shown encouraging results in transgenic animal models but less encouraging results in human trials, which have also been plagued with serious adverse events (SAEs), including amyloid-related imaging abnormalities (ARIAs). Our proposed innovative therapeutic approach is based on epidemiological evidence that patients with the inflammatory disease rheumatoid arthritis (RA) have a reduced risk of developing AD, unrelated to their use of non-steroidal anti-inflammatory drugs (NSAIDs). We identified the innate immune system stimulant Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) as a hematopoietic factor upregulated in RA, which we found reduced brain amyloidosis and reversed cognitive impairment in transgenic AD mice. Other studies have shown GM-CSF to be neuroprotective, anti-apoptotic, and neurogenic in several models of neurological diseases and injuries. We also found that recombinant human GM-CSF(sargramostim/Leukine) treatment is associated with cognitive improvements in leukemia patients after bone marrow chemo-ablation and hematopoietic cell transplant therapy. Notably, sargramostim is an FDA-approved drug for increasing the production and differentiation of white blood cells with an excellent safety record over 30 years. Most importantly, we recently completed a Phase I/II safety and efficacy trial (NCT01409915) in which mild-to-moderate AD participants were treated with sargramostim (250 mcg/m2/day SC) or placebo five days/week for three weeks (20:20 participants per group) with neurological, neuropsychological, neuroimaging, and blood biomarker assessments. Sargramostim treatment was safe (Primary Endpoint) with no drug-related SAEs and no ARIAs. Furthermore, the Mini-Mental State Exam (MMSE) showed cognitive improvement in the sargramostim group at the end of treatment (EOT) compared to baseline (p=0.0074) and in the sargramostim group compared to the placebo group at the EOT (p=0.037) and at 45 days after the EOT (p=0.0281). Other assessments showed no treatment benefits, but there was a trend negative correlation between changes in MMSE versus amyloid-PET. We now propose to carry out a randomized, double- blind, placebo-controlled trial in 42 mild-to-moderate AD participants, 28 of whom will receive sargramostim (250 mcg/m2/day SC) and 14 of whom will receive placebo, five days/week for 24 weeks with a 45-day follow-up visit. We have received both an IND exemption (134291) and IRB approval (17-0215) but will submit improved versions in the coming months.
Our Specific Aims are: 1) Assess the long-term safety and tolerability of sargramostim in mild-to-moderate AD participants (Primary Endpoint). 2) Assess the effects of sargramostim treatment on cognition and activities of daily living in mild-to-moderate AD participants (Secondary and Exploratory Endpoints). 3) Assess changes in biomarkers associated with sargramostim treatment in mild-to- moderate AD participants (Exploratory Endpoints).

Public Health Relevance

We propose a completely new therapeutic approach to Alzheimer?s disease (AD) based on the finding that patients with rheumatoid arthritis (RA) have a reduced risk of developing AD and on our identification of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) as a key factor increased in RA patients that also appears to provide protection against AD pathology and to improve cognition in mouse models of AD. This proposal builds on our recently completed clinical trial (NCT01409915) in which the standard FDA-approved dosage of a synthetic (recombinant) form of human GM-CSF (called sargramostim/Leukine) is administered to participants with mild-to-moderate AD for 15 days over a 19-day period with 45- and 90-day follow-up assessments to determine both its safety and efficacy (i.e., ability to decrease/suppress cognitive decline and AD pathology). Based on the encouraging results from this recently completed trial, which show that sargramostim treatment was safe and that the sargramostim-treated group showed an improvement in one measure of cognition compared to the placebo-treated group, we now propose a longer clinical trial to better assess the efficacy of sargramostim treatment over an extended treatment course of 24 weeks.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ryan, Laurie M
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University of Colorado Denver
Schools of Medicine
United States
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