PROJECT SUMMARY/ABSTRACT People with Down syndrome (DS) exhibit significant hypoplasia of the frontal lobe, hippocampus, and cerebellum and mild to severe intellectual disability, which challenges their ability to function independently. Any enhancement of their cognitive ability would greatly improve their quality of life and activities of daily living, but currently there are no therapeutics available for enhancing cognitive function in people with DS. This proposal aims to design and complete a clinical trial in adults with DS using recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF/sargramostim), an FDA-approved drug for increasing the production and differentiation of various white blood cells with almost 30 years of excellent safety history in numerous patient populations. In a previous retrospective study, we found that sargramostim treatment is associated with cognitive improvements in leukemia patients after bone marrow chemoablation and hematopoietic cell transplantation. In a recently concluded Phase II clinical trial (NCT01409915), we found that three weeks of sargramostim treatment was safe and well tolerated in mild-to-moderate Alzheimer’s disease (AD) participants and was associated with improvement in the MMSE, reduced biomarkers of neurodegeneration (Tau and UCH-L1), but no evidence of reduced amyloid. Furthermore, we have found that treatment with murine GM-CSF improves cognition and ameliorates astrogliosis in a mouse model of DS (which has no AD pathology), that it rapidly reverses cognitive impairment and removes some cerebral amyloid pathology in mouse models of AD, and that it improves age- related cognitive decline in aged wild-type mice. Numerous other studies have shown that GM-CSF is neuroprotective, anti-apoptotic, neurogenic, and beneficial in several neurological diseases and injuries, for example, in a clinical trial with Parkinson’s disease subjects and in animal models of stroke, spinal cord injury, and traumatic brain injury. Specifically, this proposal is designed to investigate whether treatment with sargramostim at the FDA-recommended dose is safe and tolerable in adults with DS, whether it can improve measures of cognitive function, quality of life, and activities of daily living, and whether it can reduce the Tau and UCH-L1 biomarkers in the blood that we have shown to evidence neuroinflammation and neurodegeneration in people with DS and to be reduced in AD patients by GM-CSF treatment.

PROJECT NARRATIVE People with Down syndrome (DS) exhibit mild to severe intellectual disability, which challenges their ability to function independently. Any improvement in their cognitive ability would greatly improve their activities of daily living, but currently there are no therapeutics available to improve cognitive function in people with DS. This proposal aims to design and complete a clinical trial in adults with DS using sargramostim, an FDA-approved drug for increasing the production and differentiation of various white blood cells, which has been shown in animal models of DS, Alzheimer’s disease (AD), and normal aging and in human studies of AD and chemo brain to be safe and associated with improved cognition.